Spirolactam aryl cgrp receptor antagonists

ABSTRACT

Compounds of formula I: 
     
       
         
         
             
             
         
       
     
     (wherein variables A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , E 1 , E 2 , E 3 , E 4 , E 5 , G 1 , G 2 , J and K are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

Based on pharmacological properties, these receptors are divided into atleast two subtypes, denoted CGRP₁ and CGRP₂. Human α-CGRP-(8-37), afragment of CGRP that lacks seven N-terminal amino acid residues, is aselective antagonist of CGRP₁, whereas the linear analogue of CGRP,diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selectiveagonist of CGRP₂. CGRP is a potent vasodilator that has been implicatedin the pathology of cerebrovascular disorders such as migraine andcluster headache. In clinical studies, elevated levels of CGRP in thejugular vein were found to occur during migraine attacks (Goadsby etal., Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on thesmooth muscle of intracranial vessels, leading to increasedvasodilation, which is thought to be the major source of headache painduring migraine attacks (Lance, Headache Pathogenesis: Monoamines,Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers,1997, 3-9). The middle meningeal artery, the principle artery in thedura mater, is innervated by sensory fibers from the trigeminal ganglionwhich contain several neuropeptides, including CGRP. Trigeminal ganglionstimulation in the cat resulted in increased levels of CGRP, and inhumans, activation of the trigeminal system caused facial flushing andincreased levels of CGRP in the external jugular vein (Goadsby et al.,Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the duramater in rats increased the diameter of the middle meningeal artery, aneffect that was blocked by prior administration of CGRP(8-37), a peptideCGRP antagonist (Williamson et al., Cephalalgia, 1.997, 17, 525-531).Trigeminal ganglion stimulation increased facial blood flow in the rat,which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669,93-99). Electrical stimulation of the trigeminal ganglion in marmosetproduced an increase in facial blood flow that could be blocked by thenon-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol.,2000, 129, 420-423). Thus the vascular effects of CGRP may beattenuated, prevented or reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,320-327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May etal. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, asthma(Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al.,Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. Virol., 1993,67, 5786-5791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30(8), 1794-1798); opiate withdrawal syndrome (Salmon et al., NatureNeurosci., 2001, 4(4), 357-358) morphine tolerance (Menard et al., J.Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chenet al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166,1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000,43 (3), 137-143); encephalitis, brain trauma, ischaemia, stroke,epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol.of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds.,Neurogenic Inflammation, 1996, CRC Press, Boca Raton, Fla.), neurogeniccutaneous redness, skin rosaceousness and erythema. Of particularimportance is the acute or prophylactic treatment of headache, includingmigraine and cluster headache.

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula I:

(wherein variables A¹, A², A³, A⁴, A⁵, A⁶, A⁷, E¹, E², E³, E⁴, E⁵, G¹,G², J and K are as described herein) which are antagonists of CGRPreceptors and which are useful in the treatment or prevention ofdiseases in which CGRP is involved, such as migraine. The invention isalso directed to pharmaceutical compositions comprising these compoundsand the use of these compounds and compositions in the prevention ortreatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:B is a selected from:

C₃₋₁₀cycloalkyl, phenyl, naphthyl, tetrahydronaphtliyl, indanyl,biphenyl, phenanthryl, anthryl, azepanyl, azepinyl, azetidinyl,benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl,benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl,cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, isoxazolidinyl, isothiazolidinyl, isothiazolyl,morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazolinyl,oxazolidinyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl,phthalazinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl,pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl,triazolyl and triazolinyl,

where B is linked to A¹ via a carbon atom in B andwhere B is unsubstituted or substituted with 1-5 substituentsindependently selected from R¹,R², R^(3a) and R^(3b), whereinR¹, R², R^(3a) and R^(3b) are each independently selected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (d) —C₃₋₆cycloalkyl,        -   (e) phenyl or heterocycle, wherein heterocycle is selected            from: azetidinyl, imidazolyl, oxazolyl, pyridinyl,            pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepanyl,            azepinyl, piperazinyl, pyrazolyl, pyrrolidinyl, thiazolyl,            thienyl, triazolyl, tetrazolyl, tetrahydrofuryl and            morpholinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-5 substituents each independently            selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (ii) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) halo,            -   (iv) hydroxy,            -   (v) trifluoromethyl,            -   (vi) —OCF₃,            -   (vii) oxo,            -   (viii) amino,            -   (ix) phenyl, and            -   (x) benzyl,        -   (f) —CO₂R⁹, wherein R⁹ is independently selected from:            -   (i) hydrogen,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 substituents, substituents each independently                selected from:                -   (I) halo,                -   (II) hydroxy,                -   (III) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (IV) —C₃₋₆cycloalkyl,                -   (V) phenyl, which is unsubstituted or substituted                    with 1-5 substituents each independently selected                    from:                -    (1) —C₁₋₄alkyl,                -    (2) —O—C₁₋₆alkyl,                -    (3) halo,                -    (4) trifluoromethyl, and                -    (5) —OCF₃,            -   (iii) —C₃₋₆cycloalkyl, which is unsubstituted or                substituted with 1-6 substituents, substituents each                independently selected from:                -   (I) halo,                -   (II) hydroxy,                -   (III) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (IV) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo, and                -   (V) phenyl, and            -   (iv) phenyl or heterocycle, wherein heterocycle is                selected from: pyridinyl, pyrimidinyl, pyrazinyl,                pyridazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl,                imidazolyl, triazolyl, tetrazolyl, benzimidazolyl,                benzothiazolyl, benzoxazolyl, imidazolinyl, indolinyl,                indolyl, quinolinyl, isoquinolinyl,                tetrahydroquinolinyl, isoindolinyl,                tetrahydroisoquinolinyl, tetrahydrofuryl, quinoxalinyl,                piperidinyl, piperazinyl, and morpholinyl, which phenyl                or heterocycle is unsubstituted or substituted with 1-5                substituents each independently selected from:                -   (I) halo,                -   (II) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo                -   (III) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo                -   (IV) —C₃₋₆cycloalkyl,                -   (V) oxo,                -   (VI) —CN,                -   (VII) hydroxy, and                -   (VIII) phenyl,        -   (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently            selected from:            -   (i) hydrogen,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 substituents each independently selected from:                -   (I) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) halo,                -   (III) hydroxy,                -   (IV) —OCF₃,                -   (V) —C₃₋₆cycloalkyl, and                -   (VI) phenyl,            -   (iii) —C₄₋₆cycloalkyl,            -   (iv) phenyl, which is unsubstituted or substituted with                1-5 substituents each independently selected from:                -   (I) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (III) halo,                -   (IV) hydroxy,                -   (V) trifluoromethyl,                -   (VI) —OCF₃, and                -   (VII) CN, and            -   (v) benzyl, which is unsubstituted or substituted with                1-5 substituents each independently selected from:                -   (I) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) halo, and                -   (IV) trifluoromethyl,            -   (vi) —COR⁹, and            -   (vii) —SO₂R¹²,        -   (h) —SO₂R¹², wherein R¹² is selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 fluoro,            -   (ii) —C₃₋₆cycloalkyl,            -   (iii) phenyl or heterocycle, wherein heterocycle is                selected from: pyridinyl, pyrimidinyl, pyrazinyl,                pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,                thienyl and morpholinyl,                -   which phenyl or heterocycle is unsubstituted or                    substituted with 1-5 substituents each independently                    selected from:                -   (I) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (III) halo,                -   (IV) hydroxy,                -   (V) trifluoromethyl,                -   (VI) —OCF₃, and                -   (VII) CN, and            -   (iv) benzyl, which is unsubstituted or substituted with                1-5 substituents each independently selected from:                -   (I) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (III) halo, and                -   (IV) trifluoromethyl,        -   (i) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each            independently selected from:            -   (i) hydrogen,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 substituents each independently selected from:                -   (I) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) halo,                -   (III) hydroxy,                -   (IV) —OCF₃,                -   (V) —C₃₋₆cycloalkyl, and                -   (VI) phenyl,            -   (iii) —C₅₋₆cycloalkyl, which is unsubstituted or                substituted with 1-5 halo,            -   (iv) phenyl, which is unsubstituted or substituted with                1-5 substituents each independently selected from:                -   (I) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (III) halo,                -   (IV) hydroxy,                -   (V) trifluoromethyl,                -   (VI) —OCF₃, and                -   (VII) CN, and            -   (v) benzyl, which is unsubstituted or substituted with                1-5 substituents each independently selected from:                -   (I) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (III) halo, and                -   (IV) trifluoromethyl,            -   or where R^(10a) and R^(11a) join to form a ring                selected from azetidinyl, pyrrolidinyl, piperidinyl,                azepanyl, piperazinyl and morpholinyl, which ring is                unsubstituted or substituted with 1-5 substituents each                independently selected from:                -   (I) —C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (II) —O—C₁₋₆alkyl, which is unsubstituted or                    substituted with 1-5 halo,                -   (III) halo                -   (IV) hydroxy                -   (V) phenyl, which is unsubstituted or substituted                    with 1-5 substituents each independently selected                    from:                -    (1) —C₁₋₄alkyl, which is unsubstituted or                    substituted with 1-3 halo,                -    (2) —O—C₁₋₄alkyl, which is unsubstituted or                    substituted with 1-3 halo, and                -    (3) halo,                -   (VI) benzyl, which is unsubstituted or substituted                    with 1-5 substituents each independently selected                    from:                -    (1) —C₁₋₄alkyl, which is unsubstituted or                    substituted with 1-3 halo,                -    (2) —O—C₁₋₄alkyl, which is unsubstituted or                    substituted with 1-3 halo, and                -    (3) halo,                -   (VII) —COR⁹, and                -   (VIII) —SO₂R¹²,        -   (j) trifluoromethyl,        -   (k) —OCO₂R⁹,        -   (l) —(NR^(10a))CO₂R⁹,        -   (m) —O(CO)NR^(10a)R^(11a),        -   (n) —(NR⁹)(CO)NR^(10a)R^(11a),        -   (o) —SO₂ NR^(10a)R^(11a), and        -   (p) —O—C₃₋₆cycloalkyl,    -   (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-7 substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (ii) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) halo,            -   (iv) hydroxy, and            -   (v) trifluoromethyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,        pyrrolidinyl, azetidinyl, azepanyl, thiazolyl, isothiazolyl,        oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl,        azepinyl, benzimidazolyl, benzopyranyl, benzofuryl,        benzothiazolyl, benzoxazolyl, chromanyl, furyl, imidazolinyl,        indolinyl, indolyl, quinolinyl, isoquinolinyl,        tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,        2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,        pyrazolidinyl, pyrazolyl, pyrrolyl, quinazolinyl,        tetrahydrofuryl, thiazolinyl, purinyl, naphthyridinyl,        quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl, piperidinyl,        tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, and        morpholinyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 substituents each independently selected from:            -   (a) halo,            -   (b) hydroxy,            -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (d) —C₃₋₆cycloalkyl,            -   (e) phenyl,            -   (f) —CO₂R⁹, and            -   (g) —NR¹⁰R¹¹,        -   (b) halo,        -   (c) hydroxy,        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (e) —C₃₋₆cycloalkyl,        -   (f) phenyl or heterocycle, wherein heterocycle is selected            from: pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl,            pyrimidinyl, pyrazinyl, thienyl and morpholinyl, which            phenyl or heterocycle is unsubstituted or substituted with            1-5 substituents each independently selected from:            -   (i) —C₁₋₆allyl,            -   (ii) —O—C₁₋₆alkyl,            -   (iii) halo,            -   (iv) hydroxy, and            -   (v) trifluoromethyl,        -   (g) —CO₂R⁹,        -   (h) —(CO)R⁹,        -   (i) —NR¹⁰R¹¹,        -   (j) —CONR^(10a)R^(11a),        -   (k) oxo        -   (l) —SR¹²,        -   (m) —S(O)R¹²,        -   (n) —SO₂R¹²,        -   (o) —SO₂NR^(10a)R^(11a), and        -   (p) —CN,    -   (4) halo,    -   (5) oxo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl,        -   (e) —CO₂R⁹, and        -   (f) —NR¹⁰R¹¹,    -   (8) —CN,    -   (9) —CO₂R⁹,    -   (10) —NR¹⁰R¹¹,    -   (11) —SR¹²,    -   (12) —S(O)R¹²,    -   (13) —SO₂R¹²,    -   (14) —SO₂NR^(10a)R^(11a),    -   (15) —CONR^(10a)R^(11a),    -   (16) —OCO₂R⁹,    -   (17) —(NR^(10a))CO₂R⁹,    -   (18) —O(CO)NR^(10a)R^(11a),    -   (19) —(NR⁹)(CO)NR^(10a)R^(11a),    -   (20) —(CO)—(CO)NR^(10a)R^(11a), and    -   (21) —(CO)—(CO)OR⁹;    -   or where R^(3a) and R^(3b) and the atom(s) to which they are        attached join to form a ring selected from cyclobutyl,        cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,        azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,        tetrahydrofuranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,        dihydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl,        dihydrothiopyranyl, tetrahydrothiopyranyl, imidazolyl,        imidazolinyl, and piperazinyl, which ring is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (i) halo,            -   (ii) hydroxy,            -   (iii) —O—C₁₋₆alkyl, which is unsubstituted or                substituted with 1-3 halo,            -   (iv) —C₃₋₆cycloalkyl,            -   (v) phenyl or heterocycle, wherein heterocycle is                selected from: pyridinyl, pyrimidinyl, pyrazinyl,                pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,                thienyl and morpholinyl, which phenyl or heterocycle is                unsubstituted or substituted with 1-5 substituents each                independently selected from:                -   (I) —C₁₋₆alkyl,                -   (II) —O—C₁₋₆alkyl,                -   (III) halo,                -   (IV) hydroxy,                -   (V) trifluoromethyl, and                -   (VI) —OCF₃,            -   (vi) —CO₂R⁹,            -   (vii) —NR¹⁰R¹¹,            -   (viii) —SO₂R¹²,            -   (ix) —CONR^(10a)R^(11a), and            -   (x) (NR^(10a))CO₂R⁹,        -   (b) phenyl or heterocycle, wherein heterocycle is selected            from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl,            pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and            morpholinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 fluoro,            -   (ii) halo,            -   (iii) hydroxy,            -   (iv) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 fluoro, and            -   (v) —C₃₋₆cycloalkyl,        -   (c) halo,        -   (d) —SO₂R¹²,        -   (e) hydroxy,        -   (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (g) —CN,        -   (h) —COR¹²,        -   (i) —NR¹⁰R¹¹,        -   (j) —CONR^(10a)R^(11a),        -   (k) —CO₂R⁹,        -   (l) —(NR^(10a))CO₂R⁹,        -   (m) —O(CO)NR^(10a)R^(11a), and        -   (n) —(NR⁹)(CO)NR^(10a)R^(11a);

-   A¹, A² and A³ are each independently selected from:    -   (1) a bond,    -   (2) —CR¹³R¹⁴—, wherein R¹³ and R¹⁴ are each independently        selected from:        -   (a) hydrogen,        -   (b) C₁₋₆ alkyl, which is unsubstituted or substituted with            1-5 substituents each independently selected from:            -   (i) —C₃₋₆cycloalkyl,            -   (ii) —O—C₁₋₆alkyl,            -   (iii) halo,            -   (iv) hydroxy, and            -   (v) phenyl,        -   (c) hydroxy, and        -   (d) halo,    -   (3) NR¹⁰—,    -   (4) —CR¹³R¹⁴—NR¹⁰—,    -   (5) —CR¹³R¹⁴—CH₂—,    -   (6) —CH₂—CR¹³R¹⁴—,    -   (7) —O—CR¹³R¹⁴—,    -   (8) —CR¹³R¹⁴—O—,    -   (9) —C≡C—,    -   (10) —C(R¹³)═C(R¹⁴)—, and    -   (11) —C(═O)—,    -   or wherein one or two of A¹, A² and A³ are absent,

-   A⁴, A⁵, A⁶ and A⁷ are each independently selected from:    -   (1) a bond, and    -   (2) —CR¹³R¹⁴—,    -   or wherein one of A⁴, A⁵, A⁶ and A⁷ is independently selected        from:        -   (i) —O—,        -   (ii) —C(═O)—, and        -   (iii) —N(R¹⁵)—, wherein R¹⁵ is selected from:            -   (a) hydrogen,            -   (b) C₁₋₆ alkyl, which is unsubstituted or substituted                with 1-5 substituents each independently selected from:                -   (I) hydroxy,                -   (II) —O—C₁₋₆alkyl,                -   (III) halo,                -   (IV) —C₃₋₆cycloalkyl,                -   (V) trifluoromethyl, and                -   (VI) phenyl,    -   or wherein one or both of A⁴ and A⁷ are absent;

-   E¹ and E⁵ are each independently selected from:    -   (1) ═C(R⁴)—,    -   (2) —CR⁴R⁵—,    -   (3) —C(═O)—,    -   (4) —C(═S)—,    -   (5) ═N—,    -   (6) ═N⁺(O⁻)—,    -   (7) —N(R⁴)—,    -   (8) —O—,    -   (9) —S—, and    -   (10) —SO₂—;

-   E³ and E⁴ are each independently selected from:    -   (1) a bond,    -   (2) ═C(R⁴)—,    -   (3) —CR⁴R⁵—,    -   (4) —C(═O)—,    -   (6) ═N⁺(O⁻)—,    -   (7) —N(R⁴)—, and    -   (8) —O—,    -   or wherein one or both of E³ and E⁴ are absent;

-   E² is selected from:

-   G¹ and G² are each independently selected from:    -   (1) ═C(R⁴)—,    -   (2) ═N—, and    -   (3) ═N⁺(O⁻)—;-   J is selected from:    -   (1) ═C(R^(6a))—,    -   (2) —CR¹³R¹⁴—, and    -   (3) —C(═O)—;-   K is selected from:    -   (1) ═C(R^(6b))—,    -   (2) —CR¹³R¹⁴—,    -   (3) —C(═O)—,    -   (4) —SO₂—,    -   (5) ═N—, and    -   (6) —N(R^(6b))—;-   R⁴ and R⁵ are each independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) —C₃₋₆cycloalkyl,        -   (e) phenyl,        -   (f) —CONR^(10a)R^(11a),        -   (g) —CO₂R⁹, and        -   (h) —NR¹⁰R¹¹,    -   (3) —C₃₋₆cycloalkyl,    -   (4) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (b) halo,        -   (c) hydroxy, and        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,    -   (5) halo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (8) —CN,    -   (9) —CO₂R⁹,    -   (10) —NR¹⁰R¹¹,    -   (11) —SO₂R¹²,    -   (12) —CONR^(10a)R^(11a),    -   (13) —OCO₂R⁹, and    -   (14) —(NR^(10a))CO₂R⁹;-   R^(6a) and R^(6b) are each independently selected from:    -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₆alkyl,        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein heterocycle is selected            from: imidazolyl, oxazolyl, pyridinyl, pyrimidinyl,            pyrazinyl, pyridazinyl, piperidinyl, piperazinyl,            pyrrolidinyl, thiazolyl, thienyl, triazolyl and morpholinyl,            which phenyl or heterocycle is unsubstituted or substituted            with 1-3 substituents each independently selected from:            -   (i) —C₁₋₆alkyl,            -   (ii) —O—C₁₋₆alkyl,            -   (iii) halo,            -   (iv) hydroxy,            -   (v) trifluoromethyl, and            -   (vi) —OCF₃,    -   (4) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl,        azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,        tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or        heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-5 fluoro,        -   (b) halo,        -   (c) hydroxy,        -   (d) —O—C₁₋₄alkyl, which is unsubstituted or substituted with            1-5 fluoro,        -   (e) —C₃₋₆cycloalkyl, and        -   (f) phenyl,    -   (5) halo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (8) —CN,    -   (9) —CO₂R⁹,    -   (10) —NR¹⁰R¹¹, and    -   (11) —CONR^(10a)R^(11a);    -   or where R^(6a) and R^(6b) and the atom(s) to which they are        attached join to form a ring selected from cyclopentenyl,        cyclohexenyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyridazinyl, furanyl, dihydrofuranyl, dihydropyranyl, thiazolyl,        isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl,        thienyl, dihydrothienyl and dihydrothiopyranyl, which ring is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (i) halo,            -   (ii) hydroxy,            -   (iii) —O—C₁₋₆alkyl,            -   (iv) —C₃₋₆cycloalkyl,            -   (v) phenyl or heterocycle, wherein heterocycle is                selected from: pyridinyl, pyrimidinyl, pyrazinyl,                pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,                thienyl and morpholinyl, which phenyl or heterocycle is                unsubstituted or substituted with 1-5 substituents each                independently selected from:                -   (I) —C₁₋₆alkyl,                -   (II) —O—C₁₋₆alkyl,                -   (III) halo,                -   (IV) hydroxy,                -   (V) trifluoromethyl, and                -   (VI) —OCF₃,            -   (vi) —CO₂R⁹,            -   (vii) —NR¹⁰R¹¹,            -   (viii) —SO₂R¹²,            -   (ix) —CONR^(10a)R^(11a), and            -   (x) (NR^(10a))CO₂R⁹,        -   (b) phenyl or heterocycle, wherein heterocycle is selected            from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl,            pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and            morpholinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 fluoro,            -   (ii) halo,            -   (iii) hydroxy,            -   (iv) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 fluoro, and            -   (v) —C₃₋₆cycloalkyl,        -   (c) halo,        -   (d) —SO₂R¹²,        -   (e) hydroxy,        -   (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (g) —CN,        -   (h) —COR¹²,        -   (i) —NR¹⁰R¹¹,        -   (i) —CONR^(10a)R^(11a),        -   (k) —CO₂R⁹,        -   (l) —(NR^(10a))CO₂R⁹,        -   (m) —O(CO)NR^(10a)R^(11a),        -   (n) —(NR⁹)(CO)N—R^(10a)R^(11a), and        -   (o) oxo;            and pharmaceutically acceptable salts thereof and individual            enantiomers and diastereomers thereof.

In embodiments of the invention where A¹ is CR¹³R¹⁴—, A², A³, A⁴ and A⁷are absent, A⁵ and A⁶ are —CH₂—, G¹ and G² are ═C(R⁴)—, E¹ is ═N—, E² is

E³ and E⁵ are ═C(H)—, E⁴ is absent, J is ═C(R^(6a))—, and K is═C(R^(6b))—, where R^(6a) and R^(6b) and the atoms to which they areattached are joined to form a pyridinyl ring, the following structureforms:

In embodiments of the invention where A¹ is CR¹³R¹⁴—, A², A³, A⁴ and A⁷are absent, A⁵ and A⁶ are CH₂—, G¹ and G² are ═C(R⁴)—, E⁵ is ═N—, E² is

E¹ and E³ are ═C(H)—, E⁴ is absent, J is ═C(R^(6a))—, and K is═C(R^(6b))—, where R^(6a) and R^(6b) and the atoms to which they areattached are joined to form a pyridinyl ring, the following structureforms:

In embodiments of the invention where A¹ is C(═O)—, A², A³, A⁴ and A⁷are absent, A⁵ and A⁶ are —CH₂—, G¹ and G² are ═C(R⁴)—, E¹ is ═N—, E² is

E³ and E⁵ are ═C(H)—, E⁴ is absent, J is ═C(R^(6a))—, and K is═C(R^(6b))—, where R^(6a) and R^(6b) and the atoms to which they areattached are joined to form a pyridinyl ring, the following structureforms: the following structure forms:

In embodiments of the invention where A¹ is —CR¹³R¹⁴—, A², A³, A⁴ and A⁷are absent, A⁵ and A⁶ are CH₂—, G¹ and G² are ═C(R⁴)—, E¹ and E⁵ are═N—, E² is

E³ is ═C(H)—, E⁴ is absent, J is ═C(R^(6a))—, and K is ═C(R^(6b))—,where R^(6a) and R^(6b) and the atoms to which they are attached arejoined to form a pyridinyl ring, the following structure forms:

In embodiments of the invention where A¹ is CR¹³R¹⁴, A², A³, A⁴ and A⁷are absent, A⁵ and A⁶ are —CH₂—, G¹ and G² are ═C(R⁴)—, E¹ is —N(R⁴)—,E² is

E³ and E⁴ are absent, E⁵ is ═N—, J is ═C(R^(6a))—, and K is ═C(R^(6b))—,where R^(6a) and R^(6b) and the atoms to which they are attached arejoined to form a pyridinyl ring, the following structure forms:

In embodiments of the invention where A¹ is CR¹³R¹⁴—, A², A³, A⁴ and A⁷are absent, A⁵ and A⁶ are CH₂—, G¹ and G² are ═C(R⁴)—, E¹ is —N(H)—, E²is

E³ is ═N—, E⁴ and E; are —CR⁴R⁵—, J is ═C(R^(6a))—, and K is═C(R^(6b))—, where R^(6a) and R^(6b) and the atoms to which they areattached are joined to form a pyridinyl ring, the following structureforms:

An embodiment of the present invention includes compounds of the formulaIa:

wherein A¹, A², A³, A⁴, A⁵, A⁶, A⁷, B, E¹, E², E³, E⁴, E⁵, J, K, and R⁴are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ib:

wherein A¹, A², B, E¹, E², E³, E⁴, E⁵, J, K and R⁴ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.Another embodiment of the present invention includes compounds of theformula Ic:

wherein A¹, A², B. E¹, E², E³, E⁵, J, K and R⁴ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Id:

wherein A¹, A², B. E³, E⁵, J, K and R⁴ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ie:

wherein A¹, B, E³, E⁵, J, K and R⁴ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula If:

wherein A¹, A², A³, B, E³, E⁵, J, K and R⁴ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ig:

wherein A¹, A², B, E¹, E³, J, K and R⁴ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

In an embodiment of the present invention B is selected from the groupconsisting of: C₃₋₁₀cycloalkyl, phenyl, biphenyl, naphthyl,tetrahydronaphthyl, indanyl, indolyl, indolinyl, indazolyl,isoindolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, morpholinyl,naphthyridinyl, piperidinyl, piperazinyl, pyrazinyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrahydroquinolinyl, phthalazinyl, pyrazolyl,isoxazolinyl, indazolyl, benzoxazolyl, benzoxazolinyl, benzimidazolyl,benzimidazolinyl, thiazolyl, and thienyl, which is unsubstituted orsubstituted with 1-5 substituents selected from R¹, R², R^(3a) andR^(3b), wherein R¹, R², R^(3a) and R^(3b) are defined herein.

In an embodiment of the present invention B is phenyl.

In an embodiment of the present invention B is biphenyl.

In an embodiment of the present invention B is naphthyl.

In an embodiment of the present invention B is thienyl.

In an embodiment of the present invention B is piperidinyl.

In an embodiment of the present invention B is morpholinyl.

In an embodiment of the present invention B is pyridinyl.

In an embodiment of the present invention B is quinolinyl.

In an embodiment of the present invention B is tetrahydroquinolinyl.

In an embodiment of the present invention B is quinoxalinyl.

In an embodiment of the present invention B is phthalazinyl.

In an embodiment of the present invention B is pyrrolidinyl.

In an embodiment of the present invention B is pyrazolyl.

In an embodiment of the present invention B is isoxazolinyl.

In an embodiment of the present invention B is isoxazolyl.

In an embodiment of the present invention B is quinazolinyl.

In an embodiment of the present invention B is norbornyl.

In an embodiment of the present invention B is cyclohexyl.

In an embodiment of the present invention B is cyclopentyl.

In an embodiment of the present invention B is cyclopropyl.

In an embodiment of the present invention B is thiazolyl.

In an embodiment of the present invention B is indanyl.

In an embodiment of the present invention B is indolinyl.

In an embodiment of the present invention B is indazolyl.

In an embodiment of the present invention B is indolyl.

In an embodiment of the present invention B is isoindolinyl.

In an embodiment of the present invention B is benzoxazolinyl.

In an embodiment of the present invention B is benzoxazolyl.

In an embodiment of the present invention B is benzimidazolinyl.

In an embodiment of the present invention B is benzimidazolyl.

In an embodiment of the present invention R¹, R², R^(3a) and R^(3b) areindependently selected from:

-   -   (1) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) —C₃₋₆cycloalkyl,        -   (e) phenyl or heterocycle, wherein heterocycle is selected            from: pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, or            morpholinyl,        -   (f) —(NR^(10a))CO₂R⁹, and        -   (g) NR¹⁰R¹¹,    -   (2) C₃₋₆ cycloalkyl,    -   (3) —OR⁹,    -   (4) —OCF₃,    -   (5) trifluoromethyl,    -   (6) halo,    -   (7) oxo,    -   (8) hydroxy,    -   (9) —CN,    -   (10) —COR¹²,    -   (11) —CO₂R¹²,    -   (12) —CONR^(10a)R^(11a),    -   (13) —NR¹⁰R¹¹,    -   (14) phenyl, which is unsubstituted or substituted with 1-5        substituents selected from:        -   (a) C₁₋₆alkyl,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) —OH, and        -   (e) —CF₃, and    -   (15) heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl,        piperazinyl, piperidinyl, tetrazolyl, or morpholinyl, and which        is unsubstituted or substituted with 1-5 substituents selected        from:        -   (a) C₁₋₆alkyl,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) —OH, and        -   (e) —CF₃.

In an embodiment of the present invention, R^(3a) and R^(3b) and thecarbon atom(s) to which they are attached are joined together to form aring selected from piperidinyl, cyclohexyl, cyclopentyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, andtetrahydrothiopyranyl, which is unsubstituted or substituted with 1-3substituents independently selected from:

-   -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (i) halo, and        -   (ii) phenyl,    -   (b) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl and pyrazinyl,    -   (c) —CO₂R⁹,    -   (d) hydroxy, and    -   (e) oxo.

In an embodiment of the present invention, R^(3a) and R^(3b) and thecarbon atom(s) to which they are attached join to form a ring selectedfrom piperidinyl, cyclohexyl, tetrahydropyranyl, andtetrahydrothiopyranyl, which ring is unsubstituted or substituted with1-3 substituents independently selected from:

-   -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents independently selected from:        -   (i) fluoro, and        -   (ii) phenyl,    -   (b) —CO₂—C₁₋₄alkyl,    -   (c) hydroxyl, and    -   (d) oxo.

In an embodiment of the present invention A¹ is a bond.

In an embodiment of the present invention A¹ is —CR¹³R¹⁴—.

In an embodiment of the present invention A¹ is —CH₂—.

In an embodiment of the present invention A¹ is —OCH₂—.

In an embodiment of the present invention A¹ is —C≡C—.

In an embodiment of the present invention A¹ is —CH₂—CH₂—.

In an embodiment of the present invention A¹ is —C(H)═C(H)—.

In an embodiment of the present invention A¹ is —NH—.

In an embodiment of the present invention A¹ is —C(═O)—.

In an embodiment of the present invention A² is CH₂.

In an embodiment of the present invention A² is —CH₂—NH—.

In an embodiment of the present invention A² is —C(═O)—.

In an embodiment of the present invention A² is —C═C—.

In an embodiment of the present invention A² is —NH—.

In an embodiment of the present invention A² is —CH₂—CH₂—.

In an embodiment of the present invention A² is a bond.

In an embodiment of the present invention A³ is —CH₂—.

In an embodiment of the present invention A³ is —C(—O)—.

In an embodiment of the present invention A³ is —CH₂—.

In an embodiment of the present invention A³ is —CH₂O—.

In an embodiment of the present invention A³ is a bond.

In an embodiment of the present invention A⁴ is selected from: CH₂; anda bond.

In an embodiment of the present invention A⁴ is a bond.

In an embodiment of the present invention A⁵ is CH₂.

In an embodiment of the present invention A⁶ is CH₂

In an embodiment of the present invention A⁷ is selected from: CH₂; anda bond.

In an embodiment of the present invention A⁷ is a bond.

In an embodiment of the present invention E¹ is selected from:

═C(R⁴)—; —CR⁴R⁵—; ═N—; and —N(R⁴)—; wherein R⁴ and R⁵ are definedherein.

In an embodiment of the present invention E¹ is selected from: ═N—; and—N(H)—.

In an embodiment of the present invention E⁵ is selected from:

═C(R⁴)—; —CR⁴R⁵—; ═N—; and —N(R⁴)—; wherein R⁴ and R⁵ are definedherein.

In an embodiment of the present invention E⁵ is selected from:

═C(H)—; —CH₂—; ═N—; and —N(H)—.

In an embodiment of the present invention E³ is selected from:

a bond; —C(R⁴)—; —CR⁴R⁵—; ═N—; and —N(R⁴)—; wherein R⁴ and R⁵ aredefined herein.

In an embodiment of the present invention E³ is selected from:

a bond; ═C(H)—; ═N—; and —N(H)—.

In an embodiment of the present invention E⁴ is selected from:

a bond; and —CH₂—.

In an embodiment of the present invention E⁴ is a bond.

In an embodiment of the present invention E² is selected from:

In an embodiment of the present invention E² is

In an embodiment of the present invention G¹ is ═C(R⁴)—.

In an embodiment of the present invention G¹ is ═C(H)—.

In an embodiment of the present invention G² is ═C(R⁴)—.

In an embodiment of the present invention G² is ═C(H)—.

In an embodiment of the present invention J is selected from:

═C(R^(6a))—; and —CH₂—; wherein R^(6a) is defined herein.

In an embodiment of the present invention J is —CH₂—.

In an embodiment of the present invention J is ═C(R^(6a))—; whereinR^(6a) is defined herein.

In an embodiment of the present invention K is selected from:

═C(R^(6b))—; —CH₂—; and —C(═O)—; wherein R^(6b) is defined herein.

In an embodiment of the present invention K is —CH₂—.

In an embodiment of the present invention K is ═C(R^(6b))—; whereinR^(6b) is defined herein.

In an embodiment of the present invention R⁴ and R⁵ are independentlyselected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) —C₃₋₆cycloalkyl, and        -   (e) phenyl,    -   (3) —C₃₋₆cycloalkyl,    -   (4) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro, and        -   (b) halo,    -   (5) halo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (8) —CN, and    -   (9) —NR¹⁰R¹¹;

In an embodiment of the present invention R⁴ and R⁵ are independentlyselected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (3) phenyl,    -   (5) halo, and    -   (6) hydroxy;

In an embodiment of the present invention R⁴ and R⁵ are independentlyselected from: hydrogen, halo, and methyl.

In an embodiment of the present invention R⁴ is hydrogen.

In an embodiment of the present invention R⁵ is hydrogen.

In an embodiment of the present invention R^(6a) and R^(6b) areindependently selected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₆alkyl,        -   (c) —C₃₋₆cycloalkyl, and        -   (d) phenyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,        tetrahydrofuryl, piperidinyl, and morpholinyl, which is        unsubstituted or substituted with 1-3 substituents each        independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (b) halo,        -   (c) hydroxy, and        -   (d) —O—C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro,    -   (4) halo,    -   (5) —NR¹⁰R¹¹,    -   (6) hydroxy,    -   (7) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        halo.

In an embodiment of the present invention R^(6a) and R^(6b) areindependently selected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro, and    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,        tetrahydrofuryl, piperidinyl, and morpholinyl.

In an embodiment of the present invention R^(6a) and R^(6b) and theatom(s) to which they are attached join to form a ring selected fromphenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl,oxazolyl, imidazolyl, thienyl, which is unsubstituted or substitutedwith 1-3 substituents each independently selected from:

-   -   (a) —C₁₋₄ally, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (i) halo,        -   (ii) —O—C₁₋₆alkyl,        -   (iii) —CO₂R⁹,        -   (iv) —NR¹⁰R¹¹, and        -   (v) —CONR^(10a)R^(11a),    -   (b) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl,        piperidinyl and morpholinyl, which is unsubstituted or        substituted with 1-3 substituents each independently selected        from:        -   (i) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-5 fluoro,        -   (ii) halo,        -   (iii) hydroxy, and        -   (iv) —O—C₁₋₄alkyl, which is unsubstituted or substituted            with 1-3 fluoro,    -   (c) halo,    -   (d) hydroxy,    -   (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (f) —CN,    -   (g) —NR¹⁰R¹¹,    -   (h) —CONR^(10a)R^(11a), and    -   (i) oxo.

In an embodiment of the present invention R^(6a) and R^(6b) and theatom(s) to which they are attached join to form a ring selected fromphenyl, pyridinyl, and pyrimidinyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from:

-   -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (b) halo,    -   (c) hydroxy, and    -   (d) —O—C₁₋₄alkyl.

In an embodiment of the present invention R^(6a) and R^(6b) and theatom(s) to which they are attached join to form a ring selected frompyridinyl, and pyrimidinyl.

In an embodiment of the present invention R⁹ is selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5        substituents, substituents each independently selected from:        -   (I) halo,        -   (II) hydroxy,        -   (III) —O—C₁₋₄alkyl, which is unsubstituted or substituted            with 1-3 halo,        -   (IV) —C₃₋₆cycloalkyl,        -   (V) phenyl, which is unsubstituted or substituted with 1-3            substituents each independently selected from:            -   (1) —C₁₋₄alkyl,            -   (2) —O—C₁₋₄alkyl, and            -   (3) halo,    -   (iii) —C₃₋₆cycloalkyl, which is unsubstituted or substituted        with 1-4 substituents, substituents each independently selected        from:        -   (I) halo,        -   (II) hydroxyl, and        -   (III) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 halo, and    -   (iv) phenyl or heterocycle, wherein heterocycle is selected        from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl,        imidazolyl, triazolyl, tetrazolyl, indolinyl, indolyl,        tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl,        which phenyl or heterocycle is unsubstituted or substituted with        1-3 substituents each independently selected from:        -   (I) halo,        -   (II) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-4 fluoro        -   (III) —O—C₁₋₄alkyl, which is unsubstituted or substituted            with 1-3 fluoro        -   (IV) —C₃₋₆cycloalkyl,        -   (V) oxo, and        -   (VI) phenyl.

In an embodiment of the present invention R⁹ is selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents, substituents each independently selected from:        -   (I) halo,        -   (II) hydroxy,        -   (III) —O—C₁₋₄alkyl,        -   (IV) —C₃₋₆cycloalkyl, and        -   (V) phenyl,    -   (iii) —C₃₋₆cycloalkyl, which is unsubstituted or substituted        with 1-3 substituents, substituents each independently selected        from:        -   (I) halo, and        -   (II) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro, and    -   (iv) phenyl.

In an embodiment of the present invention R¹⁰ and R¹¹ are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (I) —O—C₁₋₄alkyl,        -   (II) halo,        -   (III) hydroxy,        -   (IV) —C₃₋₆cycloalkyl, and        -   (V) phenyl,    -   (iii) —C₄₋₆cycloalkyl,    -   (iv) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo, and        -   (IV) trifluoromethyl,    -   (v) benzyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo, and        -   (IV) trifluoromethyl,    -   (vi) —COR⁹, and    -   (vii) —SO₂R¹².

In an embodiment of the present invention R¹⁰ and R¹¹ are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —O—C₁₋₄alkyl,        -   (II) halo,        -   (III) —C₃₋₆cycloalkyl, and        -   (IV) phenyl,    -   (iii) —C₄₋₆cycloalkyl,    -   (iv) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl, and        -   (II) halo,    -   (v) benzyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl, and        -   (II) halo,    -   (vi) —COR⁹, and    -   (vii) —SO₂R¹².

In an embodiment of the present invention R^(10a) and R^(11a) are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —O—C₁₋₄alkyl,        -   (II) halo,        -   (III) hydroxy,        -   (IV) —C₃₋₆cycloalkyl, and        -   (V) phenyl,    -   (iii) —C₅₋₆cycloalkyl,    -   (iv) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo, and        -   (IV) trifluoromethyl,    -   (v) benzyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo, and        -   (IV) trifluoromethyl,    -   or where R^(10a) and R^(11a) join to form a ring selected from        pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which        ring is unsubstituted or substituted with 1-4 substituents each        independently selected from:        -   (I) —C₁₋₄alkyl        -   (II) halo        -   (III) hydroxy        -   (IV) phenyl,        -   (V) benzyl,        -   (VI) —COR⁹, and        -   (VII) —SO₂R¹².

In an embodiment of the present invention R^(10a) and R^(11a) are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) fluoro,        -   (II) hydroxy, and        -   (III) phenyl,    -   (iii) —C₅₋₆cycloalkyl,    -   (iv) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl, and        -   (II) halo,    -   (v) benzyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl, and        -   (II) halo,    -   or where R^(10a) and R^(11a) join to form a ring selected from        pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which        ring is unsubstituted or substituted with 1-3 substituents each        independently selected from:        -   (I) —C₁₋₄alkyl        -   (II) halo        -   (IV) phenyl,        -   (V) benzyl, and        -   (VI) —COR⁹.

In an embodiment of the present invention R¹² is selected from:

-   -   (i) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (ii) —C₃₋₆cycloalkyl,    -   (iii) phenyl or heterocycle, wherein heterocycle is selected        from: pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl,        piperazinyl, pyrrolidinyl, thienyl and morpholinyl,        -   which phenyl or heterocycle is unsubstituted or substituted            with 1-3 substituents each independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo,        -   (IV) hydroxy,        -   (V) trifluoromethyl,    -   (iv) benzyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo, and        -   (IV) trifluoromethyl.

In an embodiment of the present invention R¹² is selected from:

-   -   (i) —C₁₋₄alkyl,    -   (ii) —C₃₋₆cycloalkyl,    -   (iii) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄alkyl, and        -   (II) halo,    -   (iv) benzyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —C₁₋₄allyl, and        -   (II) halo.

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. For example, R² is recited four times informula I, and each R² in formula I may independently be any of thesubstructures defined under R². The invention is not limited tostructures and substructures wherein each R² must be the same for agiven structure. The same is true with respect to any variable appearingmultiple time in a structure or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of the R¹⁰and R¹¹ substituents are capable of forming a ring structure. Moreover,even those substituents capable of ring formation may or may not form aring structure.

Also as appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclicstructures having no double or triple bonds. Thus C₁₋₆alkyl is definedto identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linearor branched arrangement, such that C₁₋₆alkyl specifically includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which forms aring of three or more atoms. C₀ or C₀alkyl is defined to identify thepresence of a direct covalent bond.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 4- to 7-membered monocyclic- or stable 8- to11-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic groups include, but are notlimited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazolidinone,imidazoline, imidazolinone, indoline, isochroman, isoindoline,isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine,morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane,2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine,2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine,pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran,tetrahydropyran, thiamorpholine, thiazoline, thiazolidine,thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents astable 5- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, benzothiazole,benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan,furazan, imidazole, indazole, indole, indolizine, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxidesthereof.

The term “alkoxy,” as in C₁-C₆ alkoxy, is intended to refer to includealkoxy groups of from 1 to 6 carbon atoms of a straight, branched andcyclic configuration. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The terms “bond” and “absent” are in certain instances herein usedinterchangeably to refer to an atom (or chemical moiety) which is notpresent in a particular embodiment of the invention. In suchembodiments, the atoms adjacent the “bond” or “absent” atom are simplybonded to one another. For example, in certain embodiments of theinvention described and claimed herein, where -A¹-A²-A³-links B⁴ to E²,A¹ is defined as CR¹³R¹⁴ while A² and A³ are described as “absent”. Insuch a molecule, it is understood that A¹ is bonded directly to themoiety adjacent A³, i.e. the moiety E², resulting in the sub-structureB⁴-A¹-E². The absence of a specific atom or moiety, particularly an atomor moiety which serves to link or connect other atoms or moieties, doesnot imply that such other atoms or moieties are not linked.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theexamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly,membranes (25 μg) were incubated in 1 ml of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (Millipore) that had been blocked with 0.5% polyethyleneimine for3 h. The filters were washed three times with ice-cold assay buffer,then the plates were air dried. Scintillation fluid (50 μl) was addedand the radioactivity was counted on a Topcount (Packard Instrument).Data analysis was carried out by using Prism and the K_(i) wasdetermined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973)Biochem. Pharmacol. 22, 3099-3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK-N-MC cells were grown in minimalessential medium (MEM) supplemented with 10% fetal bovine serum, 2 mML-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100units/ml penicillin and 100 μg/ml streptomycin at 37° C., 95% humidity,and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for˜18 h before assay. Cells were washed with phosphate-buffered saline(PBS, Sigma) then pre-incubated with 300 μM isobutylmethylxanthine inserum-free MEM for 30 min at 37° C. Antagonist was added and the cellswere incubated for 10 min before the addition of CGRP. The incubationwas continued for another 15 min, then the cells were washed with PBSand processed for cAMP determination according to the manufacturer'srecommended protocol. Maximal stimulation over basal was defined byusing 100 nM CGRP. Dose-response curves were generated by using Prism.Dose-ratios (DR) were calculated and used to construct full Schild plots(Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48-58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) wassubcloned into the expression vector pIREShyg2 (BD Biosciences Clontech)as a 5′NheI and 3′ PmeI fragment. Human RAMP1 (Genbank accession numberAJ0014) was subcloned into the expression vector pIRESpuro2 (BDBiosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (humanembryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/mlstreptomycin, and maintained at 37° C. and 95% humidity. Cells weresubcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS.Stable cell line generation was accomplished by co-transfecting 10 ug ofDNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks CRLR andRAMP1 expression constructs were co-transfected in equal amounts.Twenty-four hours after transfection the cells were diluted andselective medium (growth medium+300 ug/ml hygromycin and 1 ug/mlpuromycin) was added the following day. A clonal cell line was generatedby single cell deposition utilizing a FACS Vantage SE (BectonDickinson). Growth medium was adjusted to 150 ug/ml hygromycin and 0.5ug/ml puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCRLR/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 10 ug of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 μM ¹²⁵I-hCGRP (Amersham Biosciences) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (Millipore) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4). Scintillation fluid was added and theplates were counted on a Topcount (Packard). Non-specific binding wasdetermined and the data analysis was carried out with the apparentdissociation constant (K_(i)) determined by using a non-linear leastsquares fitting the bound CPM data to the equation below:

$Y_{\underset{\_}{obsd}} = \frac{\begin{matrix}{{( {Y_{\max} - Y_{\min}} )( {{\% \mspace{14mu} I_{\max}} - {\%_{I_{\min}}/100}} )} +} \\{Y_{\min} + {( {Y_{\max} - Y_{\min}} )( {100 - {\% \mspace{14mu} {I_{\max}/100}}} )}}\end{matrix}}{1 + ( {\lbrack{Drug}\rbrack/{K_{i}( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} )}^{nH}} }$

Where Y is observed CPM bound, Y_(max) is total bound counts, Y min isnon specific bound counts, (Y max−Y min) is specific bound counts, % Imax is the maximum percent inhibition, % 1 min is the minimum percentinhibition, radiolabel is the probe, and the K_(d) is the apparentdissociation constant for the radioligand for the receptor as determinedby Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 μM and incubated for 30 min at37° C. Human A-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After α-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;Amersham Biosciences). Dose response curves were plotted and IC₅₀valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(X/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K_(i) or IC₅₀ value of less than about 50 μM. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; psoriasis;encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skindiseases; neurogenic cutaneous redness, skin rosaceousness and erythema;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CGRPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with ananti-migraine agent, such as ergotamine and dihydroergotamine, or otherserotonin agonists, especially a 5-HT_(1B/1D) agonist, for examplesumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan, a 5-HT_(1D) agonist such asPNU-142633 and a 5-HT_(1F) agonist such as LY334370; a cyclooxygenaseinhibitor, such as a selective cyclooxygenase-2 inhibitor, for examplerofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; anon-steroidal anti-inflammatory agent or a cytokine-suppressinganti-inflammatory agent, for example with a compound such as ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or glucocorticoids. Similarly,the instant compounds may be administered with an analgesic such asaspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone,acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; a renin inhibitor; a granzyme Binhibitor; a substance P antagonist; an endothelin antagonist; anorepinephrin precursor; anti-anxiety agents such as diazepam,alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT₂ receptorantagonists; opiod agonists such as codeine, hydrocodone, tramadol,dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; an antidepressant, for exampleamitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine,doxepin, protriptyline, desipramine, trimipramine, or imipramine; aleukotriene antagonist, for example montelukast or zafirlukast; aninhibitor of nitric oxide or an inhibitor of the synthesis of nitricoxide.

Also, the present compounds may be used in conjunction with gap junctioninhibitors; neuronal calcium channel blockers such as civamide; AMPA/KAantagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergotalkaloids other than ergotamine and dihydroergotamine, for exampleergonovine, ergonovine, methylergonovine, metergoline, ergoloidmesylates, dihydroergocornine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocomine,ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol,metoprolol or nadolol, and the like; a MAO inhibitor, for examplephenelzine; a calcium channel blocker, for example flunarizine,diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine,lomerizine, verapamil, nifedipine, or prochlorperazine; neurolepticssuch as olanzapine, droperidol, prochlorperazine, chlorpromazine andquetiapine; an anticonvulsant such as topiramate, zonisamide,tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine,gabapentin, pregabalin or divalproex sodium; an anti-hypertensive suchas an angiotensin II antagonist, for example losartan, irbesartin,valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartanand candesartan cilexetil, an angiotensin I antagonist, an angiotensinconverting enzyme inhibitor such as lisinopril, enalapril, captopril,benazepril, quinapril, perindopril, ramipril and trandolapril; orbotulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antitussive such as caramiphen, carbetapentane, or dextromethorphan;a diuretic; a prokinetic agent such as metoclopramide or domperidone; asedating or non-sedating antihistamine such as acrivastine, azatadine,bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine,phenylpropanolamine, or pseudoephedrine. The present compounds also maybe used in conjunction with anti-emetics.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: ergotamine ordihydroergotamine; a 5-HT, agonist, especially a 5-HT_(1B/1D) agonist,in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan,almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, andother serotonin agonists; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the present invention to the otheractive ingredient(s) may be varied and will depend upon the effectivedose of each ingredient. Generally, an effective dose of each will beused. Thus, for example, when a compound of the present invention iscombined with another agent, the weight ratio of the compound of thepresent invention to the other agent will generally range from about1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinationsof a compound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, solutions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease. Oral tablets may also be formulated for immediate release, suchas fast melt tablets or wafers, rapid dissolve tablets or fast dissolvefilms.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 10 milligrams to about1000 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following schemes and examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following schemes.

The synthesis of aniline intermediates may be conducted as described inschemes 1-5. Aniline intermediates bearing a variety of substituents maybe prepared by employing appropriately substituted starting materials orby derivatization of any intermediates and/or final products as desiredby methods known in the art.

The synthesis of a representative spirolactam aniline (6) is illustratedin scheme 1. The known ethyl indane-2-carboxylate (1, Schaaf et al., J.Med. Chem. 1983, 26, 328-334) may be alkylated using allyl bromide andsodium bis(trimethylsilyl)amide to form 2. Oxidation of the allyl groupwith ozone can produce the aldehyde 3, which cyclizes to the lactam 4after treatment with ammonium acetate and sodium cyanoborohydride andheating in toluene. The reductive amination of aldehyde 3 with aminesother than ammonia may be used to provide a variety of N-protectedanalogues of lactam 4, which may facilitate subsequent chemical stepsprior to removal of the lactam protecting group. The intermediate lactammay be nitrated, for example using 70% nitric acid, and the resultingnitro compound can be reduced to provide the aniline intermediate 6,using a variety of well known methodologies, such as catalytichydrogenation. Those skilled in the art of organic synthesis willrecognize that straightforward modifications of this methodology may beused to access other spirolactam intermediates, such as those with otherlactam ring sizes. Additionally, use of an alternative starting materialto the indane 1 may be used to provide different products, such astetralin-based spirolactams.

In scheme 2, an example of the synthesis of a spirooxindole intermediateis shown.

Treatment of oxindole (7) with butyllithium andtetramethylethylenediamine, followed by a dihalide or its equivalent,e.g. 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem.1979, 44(9), 1519-1533], leads to the spirooxindole 9. The bromide maybe converted to a carboxylic acid (10) by treatment with ethylmagnesiumbromide and tert-butyllithium, and quenching of the resultingorganolithium species with carbon dioxide. A Curtius rearrangement usingdiphenylphosphoryl azide in tert-butanol, followed by deprotection withhydrochloric acid can provide the aniline 11. Alternative conditions,such as treatment of acid 10 with sodium azide in concentrated sulfuricacid, may also be used to provide aniline 11.

Scheme 3 illustrates a route to spiroimide derivative 16, usingmethodology that is similar to that shown in scheme 1. Ethylindane-2-carboxylate (1) may be alkylated with tert-butyl bromoacetateto form the diester 12. Subjection of 12 to basic, then acidic,hydrolysis conditions can provide the diacid 13. Treatment of the diacid13 with a number of different reagents can provide imide 14 or aderivative thereof. In scheme 3, heating 13 in the presence of acetylchloride, followed by reaction with ammonia affords spiroimide 14.Reaction with sodium nitrite in trifluoroacetic acid, followed byhydrogenation over palladium can provide the aniline 16.

A representative synthesis of a spiroazaoxindole intermediate is shownin scheme 4. 7-Azaindole (17) may be protected with a variety ofprotecting groups, such as the 2-(trimethylsilyl)ethoxymethyl groupshown in scheme 4. Following the method of Marfat and Carter(Tetrahedron Lett., 1987, 28, 4027-4030), treatment of 18 with pyridinehydrobromide perbromide provides the dibromoazaoxindole 19, which may bereduced to the corresponding azaoxindole 20 by reaction with zinc. Thekey alkylation of 20 with 1,2-bis(bromomethyl)-4-nitrobenzene (21, Cavaet al., J. Org. Chem. 2000, 65, 5413-5415) is carried out using cesiumcarbonate in DMF to afford the spiroazaoxindole 22. A variety of otherbases and solvents may be employed in this alkylation reaction, and useof a different alkylating agent than the dibromide shown here can leadto other products. Reduction of the nitro compound 22, for example usinghydrogenation over palladium, and a two-step deprotection affords thecorresponding aniline 24. The methodology shown in scheme 4 is notlimited to azaoxindoles such as 20, but may be applied to a variety ofsuitably protected heterocyclic systems to give the corresponding spirocompounds.

Spiroazaoxindole intermediates, such as those illustrated in scheme 4,may be resolved to give pure enantiomers using techniques familiar tothose skilled in the art. For example, chromatography of the protectedintermediate 23 on a ChiralPak OD column can be used to provide theindividual enantiomers (R)-23 and (S)-23, and these enantiomers may beconverted to the corresponding anilines [(R)-24 and (S)-24] by thetwo-step deprotection. The methodology described herein may be appliedto such enantiomerically pure aniline intermediates to give theindividual enantiomers of the compounds of the present invention.Resolution may be effected by other methodologies, such as fractionalcrystallization of diastereomeric salts, and it may be carried out onother synthetic intermediates or on the final products. Alternatively,an asymmetric synthesis of a key intermediate could be used to providean enantiomerically enriched final product.

As an example of related methodology to that described in scheme 4,using alternative conditions for the alkylation reaction, the synthesisof spirodiazaoxindole compounds is outlined in scheme 5. Publishedmethodology is used to convert 6-chloro-deazapurine into4-chloro-diazaoxindole 25, the starting material in scheme 5 (Sun etal., Biorg. Med. Chem. Lett. 2002, 12, 2153-2157).

Alkylation with dibromide 21 under similar conditions to that shown inscheme 2 may provide the spirodiazaoxindole 26. Hydrogenation at 30 psifor two hours can provide the aniline 27, while hydrogenation at higherpressure (55 psi) and longer reaction time (180 hours) can provide thedes-chloro analogue 28.

Aniline intermediates, such as those described in schemes 1-5, may beconverted to a variety of other key intermediates that are useful in thesynthesis of the compounds of the present invention. For example, scheme6 illustrates methodology for conversion of a representative anilineinto several quinoline intermediates.

Aniline 24 may be acylated with (E)-3-ethoxyacryloyl chloride andtreatment of the resulting amide with sulfuric acid leads tohydroxyquinoline 29, which can be converted to, the correspondingchloride 30 by heating in phosphorus oxychloride. Condensation ofaniline 24 with crotonaldehyde in the presence of acid and an oxidantaffords the 2-methylquinoline 31. The use of other aldehydes undersimilar conditions can lead to alternatively substituted quinolines.Oxidation of quinoline 31 with selenium dioxide can provide eitheraldehyde 32 or carboxylic acid 33, depending on the amount of oxidantused and the duration of the reaction. Reduction of aldehyde 32 withsodium borohydride provides the corresponding alcohol, and treatment ofthis with thionyl chloride may be used to give the chloride 34.Intermediates such as 30, 32, 33 and 34 may be converted to compounds ofthe present invention using a variety of known methodology. While themethodology shown in scheme 6 is exemplified using aniline 24, it isunderstood that it may be applied to a variety of aniline substrates,such as those described herein, in order to provide various quinolineintermediates.

Scheme 7 illustrates the synthesis of a useful diamine intermediate. Theaniline 23 is converted to the trifluoroacetanilide, which is subjectedto standard nitration conditions, followed by removal of the protectinggroups to give nitroaniline 35. Reduction of this nitro compound, forexample by catalytic hydrogenation, affords the phenylene diamine 36.The same nitroaniline intermediate (35) may be used to provide otheruseful diamine intermediates. Another example is shown in scheme 8, inwhich 35 is elaborated to give the 2-aminophenethylamine 42.Diazotization of the nitroaniline followed by reaction of the diazoniumsalt with potassium iodide affords 37, which may be protected with a2-(trimethylsilyl)ethoxymethyl group. The resulting iodide 38 is aversatile intermediate which may be modified through a variety of knownmethodology. For example, palladium-mediated couplings can be used togive many different products, such as the ester 39, which is obtainedwhen the coupling partner of the iodide is 2-tert-butoxy-2-oxoethylzincchloride, as shown in scheme 8. Simultaneous removal of the tert-butylester and SEM protecting groups provides the acid 40. This acid may bereduced to the alcohol, and subsequent treatment with DPPA converts thealcohol to the corresponding azide 41. Catalytic hydrogenation, or anumber of other known methodologies, can be employed to reduce both thenitro and azido moieties to give the corresponding diamine 42.

The methodology illustrated in the foregoing schemes 6-8 describes thesynthesis of some intermediates that are useful for making the compoundsof the present invention. While the examples shown involve analogues ofaniline 24, those skilled in the art will appreciate that suchmethodology may be extended to a variety of other anilines to give otheruseful intermediates. For example, scheme 9 illustrates the synthesis ofheterocyclic intermediates that are analogous to those in scheme 6 butof a more general structure.

It is understood by those skilled in the art that in some casesalternative reagents or conditions may be used to effect thetransformations in scheme 9. In some cases, additional chemical stepsmay be required to obtain the compounds of interest, or variousprotecting group strategies may be employed.

The intermediates described in schemes 6-9 may be used to synthesize thecompounds of the present invention using a variety of knownmethodologies. Some of these methodologies are illustrated in scheme 10.Standard reductive amination of an aldehyde like 47 with a suitableamine (RR′NH) may be used to obtain a final product of interest (50).Similarly, a standard coupling reaction may be used to convertcarboxylic acid 48 to amide 51, which may be another example of thepresent invention when R and R′ are selected appropriately.

Scheme 10 also illustrates the coupling of chlorides 45 and 49 with asuitable partner (XH), usually under basic conditions, to give othercompounds of the present invention (52 and 53). The precise nature ofRR′NH or XH not only determines the identity of the final compound ofinterest, but also influences the choice of conditions under which thereaction is performed. For example, reductive amination of 47 may beperformed using alternative conditions to those shown in scheme 10, suchas sodium cyanoborohydride in MeOH, depending on the exact natures of 47and the amine. Similarly, the coupling of RR′NH and acid 48 may becarried out under a variety of known conditions, such as use of analternative coupling reagent like PyBOP, or activation of the carboxylicacid as an acid anhydride or acid chloride. One skilled in the art willinfer from precedent in the chemical literature, and from those examplesgiven herein, suitable conditions for reaction of either 45 or 49 withXH, which is usually an amine, lactam or similar compound.

In some cases, compounds of the present invention may be obtained by useof the methodology shown in scheme 11. Reaction of aldehyde 47 with anappropriate organometallic species (RM), such as a Grignard reagentRMgBr, may be used to give alcohol 54. A wide variety of known couplingreactions that employ transition metal catalysts may also be used tocouple chloride 45 to a suitable partner RX to give 55. Depending uponthe nature of the desired product 55, RX may be chosen from a variety ofuseful coupling partners, such as boronic acids, halides, ororganometallic reagents. In scheme 11, a palladium catalyst is used butalternatives such as nickel catalysts may also provide the compounds ofinterest. A variety of ligands may be utilized with such metalcatalysts, as described in the literature.

Scheme 12 demonstrates how some other heterocyclic structures may beobtained from diamine precursors. The phenylenediamine 56 can be coupledto an acid RCO₂H using well known coupling reagents, such as BOP, togive an anilide intermediate which may be cyclized in situ under acidicconditions to give the benzimidazole 57. The same starting material 56can be condensed with a suitable ketoaldehyde, as shown in scheme 12, togive the quinoxaline product 58. The required ketoaldehyde may besynthesized using known methodology. It may be a derivative of one ofthe coupling partners described herein, or subsequent functionalizationafter quinoxaline formation may be required to provide the desiredcompound of the present invention. Other ring sizes may also beobtained. For example, diamine 59 reacts readily with a variety ofimidate esters to afford dihydrobenzodiazepine products of structure 60.The requisite imidate ester intermediate may be obtained using knownmethodology, such as treatment of the corresponding nitrile with analcohol under acidic conditions.

In schemes 10-12, a number of strategies for assembling the compounds ofthe present invention are illustrated. It is understood that alternativemethodologies may also be employed in the synthesis of compounds ofinterest. The exact choice of reagents, solvents, temperatures, andother reaction conditions, depends upon the nature of the intendedproduct. In some cases, appropriate protecting group strategies may beused. In other cases, further elaboration of the product shown inschemes 10-12 may be required to obtain the compound of the presentinvention. As previously stated, the identity of the coupling partner(e.g. RR′NH, XH, or RCO₂H) in schemes 10-12 must be chosen appropriatelyto give the compounds of the present invention.

Most of the coupling partners used to make the compounds of the presentinvention are readily available. They may be obtained from commercialsources or synthesized by methodology familiar to those skilled in theart and as described in the chemical literature.

Aniline intermediates, such as those described in schemes 1-5, may beconverted to a variety of other key intermediates that are useful in thesynthesis of the compounds of the present invention. For example, scheme13 illustrates methodology for conversion of a representative anilineinto a quinoline intermediate.

Aniline 24 may be converted to the corresponding aldehyde 61 bytreatment with 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propanebis(tetrafluoroborate) according to the known procedure (Tom et al.,Synthesis, 2001, 9, 1351). While the methodology shown in scheme 13 isexemplified using aniline 24, it is understood that it may be applied toa variety of aniline substrates, such as those described herein, inorder to provide various quinoline intermediates. For example, scheme 14illustrates the synthesis of heterocyclic intermediates that areanalogous to those in scheme 13 but of a more general structure.

It is understood by those skilled in the art that in some casesalternative reagents or conditions may be used to effect thetransformations in scheme 14. In some cases, additional chemical stepsmay be required to obtain the compounds of interest, or variousprotecting group strategies may be employed.

The intermediates described in scheme 14 may be used to synthesize thecompounds of the present invention using a variety of knownmethodologies. One of these methodologies is illustrated in scheme 15.Standard reductive amination of an aldehyde like 62 with a suitableamine (RR′NH) may be used to obtain a final product of interest (63).

The precise nature of RR′NH not only determines the identity of thefinal compound of interest, but also influences the choice of conditionsunder which the reaction is performed. For example, reductive aminationof 62 may be performed using alternative conditions to those shown inscheme 15, such as sodium cyanoborohydride in MeOH, depending on theexact natures of 62 and the amine.

In scheme 15, a representative strategy for assembling the compounds ofthe present invention is illustrated. It is understood that alternativemethodologies may also be employed in the synthesis of compounds ofinterest. The exact choice of reagents, solvents, temperatures, andother reaction conditions, depends upon the nature of the intendedproduct. In some cases, appropriate protecting group strategies may beused. In other cases, further elaboration of the product shown in scheme15 may be required to obtain the compound of the present invention. Aspreviously stated, the identity of the coupling partner (e.g. RR′NH) inscheme 15 must be chosen appropriately to give the compounds of thepresent invention.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. Additionally, various protecting group strategies may beemployed to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

Intermediate 1

1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-oneStep A. 1-{[2-Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) wasadded in portions over 25 min to a solution of 7-azaindole (39.8 g,0.337 mol) in DMF (200 mL) at 0° C. and the mixture was stirred for 1 h.2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was thenadded slowly over 15 min, keeping the temperature of the reactionmixture below 10° C. After 1 h, the reaction was quenched with H₂O (500mL) and the mixture was extracted with CH₂Cl₂ (5×300 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered,concentrated and dried under high vacuum to give the title compound. MS:m/z=249 (M+1).

Step B.3,3-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine from StepA (43.1 g, 0.174 mol) in dioxane (300 mL) was added dropwise over 30 minto a suspension of pyridine hydrobromide perbromide (277 g, 0.868 mol)in dioxane (300 mL). The reaction was stirred at ambient temperatureusing an overhead mechanical stirrer. After 60 min, the biphasicreaction mixture was quenched with H₂O (300 mL) and extracted withEtOAc. The aqueous layer was washed with EtOAc (2×300 mL) and thecombined organic layers were washed with H₂O (4×300 mL; the final washwas pH 5-6), then brine (300 mL), then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was immediatelydissolved in CH₂Cl₂ and the solution filtered through a plug of silica,eluting with CH₂Cl₂ until the dark red color had completely eluted fromthe plug. The filtrate was washed with saturated aqueous NaHCO₃ (400mL), then brine (400 mL), dried over MgSO₄ and concentrated in vacuo togive the title compound. MS: m/z=423 (M+1).

Step C.1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Zinc (100 g, 1.54 mol) was added to a solution of3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onefrom Step B (65 g, 0.154 mol) in THF (880 mL) and saturated aqueousammonium chloride (220 mL). After 3 h, the reaction was filtered andconcentrated in vacuo. The residue was partitioned between EtOAc and H₂Owhich resulted in the formation of a white precipitate. Both layers werefiltered through a Celite pad and the layers were separated. The aqueouslayer was washed with EtOAc (2×) and the combined organic layers werewashed with H₂O, dried over MgSO₄, filtered, and concentrated. The crudeproduct was filtered through 5a plug of silica gel eluting withEtOAc:CH₂Cl₂—1:9 and the eluant was concentrated under reduced pressureto provide the title compound. MS: m/z=265 (M+1).

Intermediate 2

1,2-Bis(bromomethyl)-4-nitrobenzene Step A.(4-Nitro-1,2-phenylene)dimethanol

4-Nitrophthalic acid (40 g, 189.5 mmol) in tetrahydrofuran (500 mL) wasadded dropwise over 1.5 h to a solution of borane-THF complex (1 M, 490mL, 490 mmol), keeping the reaction temperature between 0° C. and 5° C.After the addition, the reaction was allowed to warm slowly to ambienttemperature and stirred for 18 h. Methanol (100 mL) was added carefullyand the precipitated solid dissolved. The mixture was concentrated invacuo to about 500 mL, cooled to 0° C., and 10 N sodium hydroxide wasadded to adjust the pH to 10-11. This mixture was extracted with EtOAc(3×600 mL) and the combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound. MS: m/z=207 (M−OH+CH₃CN).

Step B. 1,2-Bis(bromomethyl)-4-nitrobenzene

Phosphorus tribromide (3.9 mL, 41.1 mmol) in ether (50 mL) was addeddropwise over 1.5 h to a solution of (4-nitro-1,2-phenylene)dimethanolfrom Step A (6.85 g, 37.4 mmol) in ether (150 mL). After 18 h, thereaction mixture was cooled to 0° C. and quenched with H₂O (25 mL). Thelayers were separated and the organic layer was washed with H₂O, thensaturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, and concentratedin vacuo to give the title compound. MS: m/z=309 (M+1).

Intermediate 3

(S)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneStep A.(±)-5-Nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H1-one

To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene (40.9 g, 132 mmol,described in Intermediate 2) and1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(31.5 g, 119 mmol, described in Intermediate 1) in DMF (2 L) was addedcesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h,acetic acid (7.6 mL) was added and the mixture was concentrated to avolume of about 500 mL, then partitioned between EtOAc (1.5 L) and H₂O(1 L). The organic layer was washed with H₂O (1 L), then brine (500 mL),then dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS:m/z=412 (M+1).

Step B.(S)-5-Amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of 10% Pd/C (3 g) and(i)-5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step A (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL)under an atmosphere of hydrogen (cd. 1 atm). After 18 h, the mixture wasfiltered through a pad of Celite, washing extensively with MeOH, and thefiltrate was concentrated in vacuo to give the crude racemic compound.The enantiomers were resolved by HPLC, utilizing a Chiralcel OD columnand eluting with MeOH. The first major peak to elute was(S)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound, and the second major peak to elute was(R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one.MS: m/z=382 (M+1).

Step C.(S)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A solution of(S)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step B (13.7 g, 35.9 mmol) in methanol (300 mL) was saturated withHCl (g). The mixture was resaturated with HCl (g) every 30 min until thestarting material was consumed, and then concentrated in vacuo. Theresidue was dissolved in MeOH (150 mL) and treated with ethylenediamine(2.4 mL, 35.9 mmol) and 10 N sodium hydroxide (7.2 mL, 72 mmol) toadjust the mixture to pH 10. After 30 min, the mixture was diluted withH₂O (400 mL) and extracted with CHCl₃ (2×1 L). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude material was triturated with MeOH (50 mL) to give the titlecompound. MS: m/z=252 (M+1).

Intermediate 4

(±)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

Essentially following the procedures described for Intermediate 3, butwithout the chiral HPLC resolution of(±)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound was obtained. MS: m/z=252 (M+1).

Intermediate 5

(±)-5-Amino-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-oneStep A.5,5-Dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Pyridine hydrobromide perbromide (15.6 g, 48.8 mmol) was added in threeportions to a stirred solution of 6-chloro-7-deazapurine (2.5 g, 16.3mmol) at 40° C. in tert-butanol (100 mL). After 3 h, an additionalamount of pyridine hydrobromide perbromide (5.19 g, 16.3 mmol) wasadded. After a further 2 h, the reaction mixture was concentrated invacuo and partitioned between EtOAc and H₂O. The aqueous solution wasextracted with EtOAc (2×) and the combined organic layers were washedwith H₂O, dried over Na₂SO₄, filtered, and concentrated in vacuo to givethe title compound. MS: m/z=328 (M+1).

Step B. 4-Chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Zinc (6.05 g, 92.56 mmol) was added to a solution of5,5-dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one fromStep A (3.03 g, 9.26 mmol) in THF (20 mL) and saturated aqueous ammoniumchloride (5 mL). After 3 h, the reaction mixture was concentrated invacuo and purified by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound. MS: m/z=170 (M+1).

Step C.(±)-4′-Chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

Butyllithium (2.5 M in hexanes, 0.29 ml, 0.74 mmol) was added to astirred solution of4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition ofbutyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77mmol) was added. After 1 h at −78° C.,1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described inIntermediate 2) was added and the reaction warmed to ambienttemperature. After 8 h, the reaction was quenched with H₂O and themixture was partitioned between EtOAc and H₂O. The aqueous solution wasextracted with EtOAc (3×20 mL). The combined organic extracts werewashed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=317 (M+1).

Step D.(±)-5-Amino-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

To a solution of(±)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-onefrom Step C (400 mg, 1.26 mmol) in EtOAc (40 mL) and MeOH (10 mL) wasadded triethylamine (0.88 mL, 6.315 mmol). The mixture was hydrogenatedat 50 psi hydrogen over 10% Pd/C (100 mg). After 24 h and 90 h, anadditional amount of palladium on carbon (100 mg) was added to thereaction mixture and hydrogenation was continued for a total of 180 h.The reaction mixture was filtered through a pad of Celite andconcentrated in vacuo. The residue was purified by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound. MS: m/z=253 (M+1).

Intermediate 6

(±)-5-Amino-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one Step A.Ethyl 2-allylindane-2-carboxylate

To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med.Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C.was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7mmol) dropwise over 20 min. The resulting yellow solution was stirredfor 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5min. Stirring was continued for 1.5 h at −78° C., and then the reactionwas quenched by the addition of saturated NH₄Cl and warmed to ambienttemperature. The reaction mixture was partitioned between saturatedNH₄Cl (100 mL) and EtOAc (100 mL). The aqueous phase was furtherextracted with EtOAc (2×50 mL), and the combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude product was purified by silica gel chromatography, elutingwith a gradient of hexane:EtOAc—100:0 to 75:25, to give the titlecompound. MS: m/z=231 (M+1).

Step B. Ethyl 2-(2-oxoethyl)indane-2-carboxylate

Ethyl 2-allylindane-2-carboxylate from Step A (3.00 g, 13.0 mmol) wasdissolved in CH₂Cl₂ (100 mL) and cooled to −78° C. Ozone was bubbledthrough the solution for 15 min, at which time a light blue colorpersisted. Triethylamine (3.63 mL, 26.1 mmol) was added and the reactionmixture was stirred at ambient temperature for 1.5 h. The reactionmixture was partitioned between saturated NaHCO₃ (100 mL) and CH₂Cl₂(100 mL). The aqueous phase was further extracted with CH₂Cl₂ (2×50 mL),and the combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the title compound. MS:m/z=233 (M+1).

Step C. 1,3-Dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one

Ethyl 2-(2-oxoethyl)indane-2-carboxylate from Step B (3.03 g, 13.0 mmol)and ammonium acetate (50.2 g, 651 mmol) were stirred in AcOH (20 mL) andMeOH (20 mL) at ambient temperature for 4 h, then sodiumcyanoborohydride (1.29 g, 19.5 mmol) was added and stirring continuedfor 16 h. The reaction mixture was concentrated in vacuo and partitionedbetween saturated NaHCO₃ (50 mL) and CH₂Cl₂ (50 mL). The aqueous phasewas further extracted with CH₂Cl₂ (2×25 mL), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to yield a yellow oil. The crude oil was heated to reflux intoluene (100 mL) for 1.5 h and then concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:0 to 90:10, to give the title compound. MS:m/z=188 (M+1).

Step D. (±)-5-Nitro-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one

To 1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one from Step C (114mg, 0.609 mmol), cooled in an ice bath, was added 70% HNO₃ (5 mL). Thereaction mixture was stirred for 45 min, diluted with water (10 mL), andextracted with CH₂Cl₂ (3×10 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:EtOAc—100:0 to 50:50, to give the title compound. MS:m/z=233 (M+1).

Step E. (±)-5-Amino-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one

To a solution of(±)-5-nitro-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one fromStep D (97.0 mg, 0.418 mmol) in MeOH (5 mL) was added 10% Pd/C (15 mg).The reaction mixture was stirred under a hydrogen atmosphere (ca. 1 atm)for 1.5 h, then filtered through a Celite pad and concentrated underreduced pressure to give the title compound. MS: m/z=203 (M+1).

Intermediate 7

(±)-5-Amino-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one Step A.(±)-5-Bromo-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′)-one

To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL)was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) dropwise,followed by the dropwise addition of tetramethylethylenediamine (0.905mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then asolution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J.Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) wasadded dropwise. The reaction solution was stirred at −10 to −20° C. for2 h and at ambient temperature for 16 h. The reaction mixture waspartitioned between saturated NH₄Cl (50 mL) and EtOAc (50 mL). Theaqueous phase was further extracted with EtOAc (2×50 mL), and thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 50:50, to give the title compound. MS: m/z=315 (M+1).

Step B.(i)-2′-Oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indole]-5-carboxylicacid

To a solution of(±)-5-bromo-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one from Step A(220 mg, 0.700 mmol) in THF (2 mL) was added ethylmagnesium bromide (3.0M in ether, 0.467 mL, 1.40 mmol) dropwise, maintaining the reactiontemperature<−60° C. Then tert-butyllithium (1.7 M in pentane, 1.65 mL,2.80 mmol) was added dropwise, maintaining the reaction temperature<−60°C. The reaction solution was stirred for 5 min at −78° C., then CO₂(g)was bubbled through the solution for 15 min. Added H₂O (5 mL) and warmedto ambient temperature. The reaction mixture was partitioned betweenEtOAc (20 mL) and saturated NaHCO₃ (20 mL). The organic layer wasfurther extracted with saturated NaHCO₃ (2×10 mL). The combined aqueouslayers were washed with EtOAc (10 mL) and then acidified with 12 M HCl.The combined aqueous layers were extracted with CH₂Cl₂ (5×10 mL). Awhite precipitate formed that was insoluble in either layer, and wascollected by filtration. The combined CH₂Cl₂ layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. This crudeproduct was combined with the recovered precipitate to give the titlecompound. MS: m/z=280 (M+1).

Step C. (±)-tert-Butyl(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5 μl carbamate

A solution of(±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indole]-5-carboxylicacid from Step B (65.0 mg, 0.233 mmol), diphenylphosphoryl azide (0.060mL, 0.279 mmol), and triethylamine (0.039 mL, 0.279 mmol) in t-BuOH (5mL) was heated to reflux for 3 h. The reaction mixture was concentratedin vacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give thetitle compound. MS: m/z=295 (M-C₄H₇).

Step D. (±)-5-Amino-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one

HCl (g) was bubbled through a solution of (i)-tert-butyl(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)carbamate fromStep C (19.0 mg, 0.054 mmol) in EtOAc (5 mL) for 15 min. The reactionmixture was stirred at ambient temperature for 1 h and then concentratedin vacuo to give the title compound. MS: m/z=251 (M+1).

Intermediate 8

(±)-5-Amino-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dioneStep A. Ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate

To a solution of ethyl indane-2-carboxylate (Schaaf et al., J. Med.Chem. 1983, 26, 328-334) (2.00 g, 10.5 mmol) in THF at −78° C. was addedsodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF,15.8 mmol) dropwise, over 10 min. The mixture was stirred for 15 min,then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added dropwise,over 30 min. The resulting mixture was stirred for 30 min at −78° C.,then poured into brine (20 mL) and extracted with EtOAc (50 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give thetitle compound. MS: m/z=368 (M+Na+CH₃CN).

Step B. 2-(2-tert-Butoxy-2-oxoethyl)indane-2-carboxylic acid

A mixture of ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate fromStep A (2.48 g, 8.15 mmol) and 1.0 N sodium hydroxide (8.96 mL, 8.96mmol) in THF (50 mL), H₂O (10 mL), and EtOH (20 mL) was stirred atambient temperature for 18 h. The mixture was acidified withhydrochloric acid to about pH 3 and extracted with EtOAc (3×50 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo, to give the title compound. MS: m/z=340(M+Na+CH₃CN).

Step C. 2-(Carboxymethyl)indane-2-carboxylic acid

A solution of 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylic acid fromStep B (1.50 g, 5.43 mmol) in EtOAc (100 mL) was saturated with HCl (g)and stood at ambient temperature for 1b, then concentrated to dryness invacuo, to give the title compound. MS: m/z=284 (M+Na+CH₃CN).

Step D. 1,3-Dihydro-2H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione

A solution of 2-(carboxymethyl)indane-2-carboxylic acid from Step C(1.10 g, 4.99 mmol) in acetyl chloride (18 mL) was heated at reflux for18 h, then concentrated in vacuo. The residue was recrystallized fromtoluene to give 1′,3′-dihydrospiro[furan-3,2′-indene]-2,5(4H)-dione asan ivory solid. This solid was dissolved in CH₂Cl₂ (25 mL) and NH₃ (g)was bubbled into the mixture for 20 min. After a further 30 min, thesolvent was evaporated under reduced pressure. The resulting solid wasdried under high vacuum for 1 h, then resuspended in acetyl chloride (20mL) and heated to reflux for 18 h. The solvent was removed in vacuo andthe crude solid was recrystallized from EtOH:Et₂O to afford the titlecompound. MS: m/z=202 (M+1).

Step E.(±)-5-Amino-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione

To a solution of1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione from StepD (400 mg, 1.99 mmol) in CF₃CO₂H (10 mL) was added sodium nitrite (411mg, 5.96 mmol) and the mixture was heated to 55° C. for 2 h. The mixturewas cooled and diluted with H₂O (10 mL), then extracted with EtOAc (2×30mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo, to give(±)-5-nitro-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione,which contained some of the isomeric(±)-4-nitro-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione.This solid was dissolved in EtOH (30 mL), then AcOH (0.55 mL) and 10%Pd/C (55 mg) were added. The mixture was stirred vigorously under anatmosphere of hydrogen (ca. 1 atm) for 2 h, then filtered through a padof Celite, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc—95:5to 10:90, to give the title compound. MS: m/z=217 (M+1).

Intermediate 9

(S)-5-(Methylamino)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of(S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(154 mg, 0.613 mmol, described in Intermediate 3) and1-(hydroxymethyl)benzotriazole (93 mg, 0.625 mmol) in EtOH (2 mL) andDMF (0.2 mL) was heated at reflux for 4 h, then concentrated to drynessunder reduced pressure. The residue was resuspended in THF (3 mL) andsodium borohydride (40 mg, 1.05 mmol) was added. The resulting mixturewas heated to 70° C. for 6 h then quenched with H₂O (50 mL) andextracted with EtOAc (50 mL). The organic extract was dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0to 80:20, to give the title compound, which was of sufficient purity foruse in the next step. MS: m/z=266 (M+1).

Intermediate 10

(S)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]-quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehydeStep A.(±)-2-Methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′H)-one

(S)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(6.10 g, 24.3 mmol, described in Intermediate 3) and p-chloranil (5.97g, 24.3 mmol) were suspended in a mixture of 1-BuOH (6 mL) and conc.hydrochloric acid (6 mL, 73 mmol) and the mixture was heated to reflux.Crotonaldehyde (2.04 g, 29.1 mmol) in 1-BuOH (4 mL) was added dropwiseover 20 min. After a further 20 min at reflux, the mixture was allowedto cool to ambient temperature and 10 N NaOH (7.3 mL, 73 mmol) was addedand the neutralized mixture was concentrated in vacuo to give a brownresidue. The crude product was purified by silica gel chromatography,eluting with a gradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to 95:4.5:0.5, togive the title compound. MS: m/z=302 (M+1).

Step B.(S)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde

A mixture of(S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step A (1.30 g, 4.31 mmol) and selenium dioxide (718 mg, 6.47 mmol)in dioxane (50 mL) and H₂O (5 mL) was heated at reflux for 4 h. Thereaction mixture was concentrated to dryness under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH-100:0 to 90:10. Product-containing fractionswere combined, toluene was added, and the mixture was concentrated invacuo to give the title compound. MS: m/z=316 (M+1).

Intermediate 11

(S)-2-(Chloromethyl)-6,8-dihydrospiro[cyolopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H-oneStep 2 A.(S)-2-(Hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H-one

To a stirred suspension of(S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde(80 mg, 0.25 mmol, described in Intermediate 10) in a mixture of MeOH (5mL) and DMSO (1 mL) was added sodium borohydride (19 mg, 0.51 mmol). Theresulting mixture was stirred at ambient temperature for 1 h, then theMeOH was removed in vacuo. The residue was partitioned between saturatedaqueous NaHCO₃ (20 mL) and CH₂Cl₂ (20 mL). The aqueous layer wasextracted further with CH₂Cl₂ (2×20 mL). The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated in vacuo to give thetitle compound in sufficient purity for use in the next step. MS:m/z=318 (M+1).

Step B.(M)-2-(Chloromethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a stirred solution of(S)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step A (203 mg, 0.64 mmol) in CH₂Cl₂ (20 mL) was added thionylchloride (761 mg, 6.40 mmol) and the resulting mixture was stirred atambient temperature for 1 h, then concentrated in vacuo. The residue waspartitioned between saturated aqueous NaHCO₃ (20 mL) and CH₂Cl₂ (30 mL).The aqueous layer was extracted further with CH₂Cl₂ (2×30 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound in sufficient purityfor use in the next step. MS: m/z=336 (M+1).

Intermediate 12

(S)-2-(Chloromethyl)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneStep A.(S)-2-(Hydroxymethyl)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a stirred solution of(S)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(1.67 g, 5.26 mmol, described in Intermediate 11) in DMF (10 mL) at 0°C. was added sodium hydride (60% dispersion in mineral oil; 210 mg, 5.26mmol) and the mixture was stirred for 30 min.2-(Trimethylsilyl)ethoxymethyl chloride (0.93 mL, 5.26 mmol) was thenadded dropwise. After 90 min, the reaction was quenched with saturatedaqueous NaHCO₃ (50 mL) and the mixture was extracted with CH₂Cl₂ (3×100mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, concentrated in vacuo. The crude product was purifiedby silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH:NH₄OH-100:0:0 to 90:9:1, to give the title compound. MS:m/z=448 (M+1).

Step B.(S)-2-(Chloromethyl)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a stirred solution of(s)-2-(hydroxymethyl)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step A (1.44 g, 3.22 mmol) in CH₂Cl₂ (10 mL) was added thionylchloride (7.66 g, 64.3 mmol) and the resulting mixture was stirred atambient temperature for 30 min, then concentrated in vacuo. The residuewas concentrated in vacuo from toluene (2×10 mL) to give the titlecompound in sufficient purity for use in the next step. MS: m/z=466(M+1).

Intermediate 13

5,6-Diamino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′)-oneStep A.(S)-5-Amino-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a suspension of(R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(28.7 g, 75.2 mmol, described in Intermediate 3) in CH₂Cl₂ (100 mL) wasadded trifluoroacetic anhydride (106 mL, 752 mmol). The mixture wasstirred for 10 min, after which time the aniline had been converted tothe corresponding trifluoroacetanilide. The resulting mixture was cooledin an ice-salt bath and 15.8 M nitric acid (5.0 mL, 79 mmol) was addeddropwise over 15 min, keeping the reaction temperature at 10-12° C.After the addition, the reaction mixture was stirred for 30 min, thenH₂O (12 mL) was carefully added, followed by trifluoroacetic acid (100mL) and CH₂Cl₂ (100 mL). The mixture was allowed to warm to ambienttemperature and stirring was continued for 2 h, followed byconcentration to dryness in vacuo. The residue was dissolved in MeOH(200 mL) and the solution was adjusted to pH 10 by addition of 10 NNaOH. Ethylene diamine (5 mL, 75 mmol) was added and the mixture wasstirred at ambient temperature for 18 h, then diluted with H₂O (200 mL).The resulting solid was isolated by filtration, washed with H₂O, anddried in vacuo to give the title compound. MS: m/z=297 (M+1).

Step B.5,6-Diamino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1H)-one

A mixture of 10% Pd/C (900 mg) and(S)-5-amino-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step A (3.00 g, 10.11 mmol) was stirred vigorously in MeOH (500 mL)and EtOAc (700 mL) under an atmosphere of hydrogen (ca. 1 atm). After 18h, the mixture was filtered through a pad of Celite, washing with MeOH,and the filtrate was concentrated in vacuo to give the title compound.MS: m/z=267 (M+1).

Intermediate 14

(S)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid Step A.(S)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid

A mixture of(S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(500 mg, 1.66 mmol, described in Intermediate 10) and selenium dioxide(552 mg, 4.97 mmol) in dioxane (30 mL) and H₂O (3 mL) was heated atreflux for 18 h. The reaction mixture was allowed to cool, then it wasfiltered through a pad of Celite, and the filtrate was concentrated invacuo to give the title compound. MS: m/z=332 (M+1).

Intermediate 15

(2S-5-Amino-6-(2-aminoethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

Step A.(2R)-5-Iodo-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a suspension of(S)-5-amino-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(6.14 g, 20.7 mmol, described in Intermediate 13) in 3 N hydrochloricacid (50 mL) and THF (20 mL), at −5° C., was added NaNO₂ (1.60 g, 23.2mmol) in H₂O (10 mL) dropwise at such a rate that the reactiontemperature was maintained below 0° C. After a further 15 min, KI (9.2g, 55 mmol) in H₂O (9 mL) was added dropwise over 30 min, keeping thereaction temperature below 0° C. After a further 15 min, the mixture wasextracted with CH₂Cl₂ (3×300 mL), and the combined organic layers weredried over Na₂SO₄, decanted, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:0 to 90:10, to give the title compound,which was of sufficient purity for use in the next step. MS: m/z=408(M+1).

Step B.(2R)-5-Iodo-6-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

Sodium hydride (60% dispersion in mineral oil; 525 mg, 13.1 mmol) wasadded to a solution of(2R)-5-iodo-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′)-onefrom Step A (5.14 g, 12.6 mmol) in DMF (40 mL) at 0° C. and the mixturewas stirred for 5 min. 2-(Trimethylsilyl)ethoxymethyl chloride (2.23 mL,12.6 mmol) was then added dropwise, and the reaction mixture was stirredat 0° C. for 2 h. The reaction was quenched with dilute aqueous NaHCO₃(200 mL) and the mixture was extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—100:0 to 0:100, to give the title compound, which was ofsufficient purity for use in the next step. MS: m/z=538 (M+1).

Step C. tert-Butyl((2S)-6-nitro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetate

To a flask containing(2R)-5-iodo-6-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′.H)-onefrom Step B (4.02 g, 7.48 mmol), tris(dibenzylideneacetone)dipalladium(349 mg, 0.38 mmol), and1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (532 mg, 0.75mmol) was added 2-tert-butoxy-2-oxoethylzinc chloride (Rieke, 0.5 M inEt₂O; 15.7 mL, 7.85 mmol) and the resulting solution was heated to 40°C. for 1 h. The reaction was quenched with dilute aqueous NaHCO₃ (100mL) and the mixture was extracted with EtOAc (200 mL). The organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100,to give the title compound, which was of sufficient purity for use inthe next step. MS: m/z=526 (M+1).

Step D.[(2S)-6-Nitro-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]aceticacid

A solution of tert-butyl((2S)-6-nitro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetatefrom Step C (2.01 g, 3.83 mmol) in MeOH (25 mL) was saturated with HCl(g) and stood at ambient temperature for 18 h. The mixture wasconcentrated to dryness in vacuo, then redissolved in MeOH (25 mL). Thisstirred solution was adjusted to pH 10 with 10 N NaOH and ethylenediamine (0.26 mL, 3.83 mmol) was added. The resulting mixture wasstirred for 3 h, then concentrated to dryness in vacuo. The residue wasdissolved in THF (25 mL) and 1 N NaOH (25 mL, 25 mmol) was added. Themixture was stirred at ambient temperature for 18 h, then the THF wasremoved under reduced pressure. The residual mixture was partitionedbetween saturated aqueous NaHCO₃ (50 mL) and EtOAc (100 mL). The organiclayer was discarded and the aqueous layer was adjusted to pH 2 withaqueous HCl, then extracted with EtOAc (3×200 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give the title compound. MS: m/z=340 (M+1).

Step E.(2S)-5-(2-Hydroxyethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a stirred solution of[(2S)-6-nitro-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]aceticacid from Step D (753 mg, 2.22 mmol) in THF (15 mL), at −78° C., wasadded borane (1 M in THE; 9.1 mL, 9.1 mmol) dropwise. After 5 min, themixture was warmed to 0° C. and stirring was continued at thistemperature for 3 h. The reaction was quenched carefully with 1 N HCland stirring was continued at ambient temperature. The mixture wasadjusted to pH 8 with saturated aqueous NaHCO₃ and extracted with EtOAc(2×100 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH—100:0 to 80:20, to give the title compound. MS: m/z=326(M+1).

Step F.(2S)-5-(2-Azidoethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a stirred solution of(2S)-5-(2-hydroxyethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′-onefrom Step E (174 mg, 0.54 mmol) in DMF (4 mL) were added diphenylphosphoryl azide (177 mg, 0.64 mmol) and DBU (0.096 mL, 0.64 mmol). Themixture was heated at 100° C. for 6 h, then quenched with H₂O (20 mL)and extracted with EtOAc (50 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:0 to 80:20, to give the title compound. MS:m/z=351 (M−1).

Step G.(25)-5-Amino-6-(2-aminoethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of(2S)-5-(2-azidoethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step F (236 mg, 0.67 mmol) in EtOH (15 mL) was added 10% Pd/C (172mg). The reaction mixture was stirred under a hydrogen atmosphere (ca. 1atm) for 5 h, then filtered through a Celite pad, washing with MeOH, andthe filtrate was concentrated under reduced pressure to give the titlecompound. MS: m/z/z 295 (M+1).

Intermediate 18

(±)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-h]pyridine]-2-carbaldehyde

Essentially following the procedures described for Intermediate 10, butusing(±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(described in Intermediate 4) in place of(S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound was obtained. MS: m/z=316 (M+1).

Intermediate 19

(±)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid

Essentially following the procedures described for Intermediate 14, butusing(±)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(described in Intermediate 18) in place of(S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound was obtained. MS: m/z=332 (M+1).

Intermediate 20

(±)-2-Chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneStep A.(±)-(2E)-3-Ethoxy-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acrylamide

To a stirred suspension of(±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(3.06 g, 12.2 mmol, described in Intermediate 4) in CH₂Cl₂ (100 mL) andpyridine (40 mL) was added a solution of (E)-3-ethoxyacryloyl chloride[Tietze et al., Synthesis, 1993, 1079-1080] (1.64 g, 12.2 mmol) inCH₂Cl₂ (100 mL). The resulting mixture was stirred at ambienttemperature for 1 h, then concentrated to dryness in vacuo. The residuewas suspended in H₂O (350 mL) with sonication and the solid was isolatedby filtration and dried to give the title compound. MS: m/z=350 (M+1).

Step B.(±)-2-Hydroxy-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2(1′H)-one

To stirred concentrated sulfuric acid (25 mL) at 0° C. was added(O)-(2E)-3-ethoxy-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3-pyrrolo[2,3-b]pyridin]-5-yl)acrylamidefrom Step A (2.20 g, 6.30 mmol) portionwise. The resulting mixture wasstirred at 0° C. for 10 min then poured onto ice and adjusted to pH=9 bycareful addition of 10 N aqueous NaOH. The precipitate was isolated byfiltration, washed with H₂O, and dried to give the title compound. MS:m/z=304 (M+1).

Step C.(±)-2-Chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A solution of(±)-2-hydroxy-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step B (3.00 g, 9.89 mmol) in POCl₃ (30 mL) was stirred at 80° C.for 2 h, then concentrated to dryness under reduced pressure. Theresidue was partitioned between saturated aqueous NaHCO₃ (200 mL) andCH₂Cl₂ (500 mL). The aqueous layer was extracted further with CH₂Cl₂(200 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure to give the title compound. MS:m/z=322 (M+1).

Intermediate 21

(7S)-2-Chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

Essentially following the procedures described for Intermediate 20, butusing(s)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(described in Intermediate 3) in place of(±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound was obtained. MS: m/z=322 (M+1).

Intermediate 22

(±)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-3-carbaldehyde

(±)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(125 mg, 0.500 mmol, described in Intermediate 4) and2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propanebis(tetrafluoroborate) (266 mg, 0.750 mmol) were suspended in glacialacetic acid and the mixture was heated to reflux for 22 h. The mixturewas allowed to cool to ambient temperature before the bulk of the aceticacid was removed in vacuo. THF (3 mL) and 1 N HCl (3 mL, 3 mmol) wereadded and the mixture was stirred at ambient temperature for 2 h. Themixture was then poured into a separatory funnel containing CHCl₃ (50mL) and saturated aqueous NaHCO₃ (10 mL). The aqueous layer wasextracted twice with CHCl₃ (2×250 mL) and the combined organic layerswere dried over Na₂SO₄. Filtration to remove drying agent gave asolution which was concentrated in vacuo to give a yellow residue. Theimpure product was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:1 to 92:8, to give the title compound. MS:m/z=316 (M+1).

Intermediate 23

(7S)-2′-Oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-3-carbaldehyde

Essentially following the procedures described for Intermediate 22, butusing(s)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(described in Intermediate 3) in place of(±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-]pyridin]-2′(1′H)-one,the title compound was obtained. MS: m/z=316 (M+1).

Example 1

(7S)-2-[(Benzylaminomethyl)methyl]-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a stirred solution of(S)-2-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde(20 mg, 0.063 mmol, described in Intermediate 10), benzylamine (10 mg,0.095 mmol), and AcOH (0.018 mL, 0.315 mmol) in 1,2-dichloroethane (1mL) was added sodium triacetoxyborohydride (20 mg, 0.095 mmol). After 3h, the mixture was concentrated to dryness in vacuo and the residue waspurified by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. The pure,product-containing fractions were combined and concentrated to give thetitle compound as the trifluoroacetate salt. MS: m/z=407 (M+1). HRMS:m/z=407.1875; calculated m/z=407.1867 for C₂₆H₂₃N₄O.

Example 2

(7S)-2-(Phenoxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of phenol (11 mg, 0.12 mmol) in DMF (0.3 mL), at ambienttemperature, was added potassium carbonate (21 mg, 0.15 mmol). Theresulting mixture was stirred for 30 min, then(S)-2-(chloromethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(20 mg, 0.060 mmol, described in Intermediate 11) was added and theresulting mixture was stirred at ambient temperature for 18 h. Thereaction mixture was purified directly by HPLC using a reversed phaseC18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to5:95:0.1. The pure, product-containing fractions were combined andconcentrated to give the title compound as the trifluoroacetate salt.MS: m/z=394 (M+1). HRMS: m/z=394.1549; calculated m/z=394.1550 forC₂₅H₂₀N₃O₂

Example 3

(7S)-2′-Oxo-N-phenyl-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxamide

A mixture of(S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid (15 mg, 0.045 mmol, described in Intermediate 14), aniline (4 mg,0.045 mmol), EDC (26 mg, 0.136 mmol), HOBT (21 mg, 0.136 mmol), andN,N-diisopropylethylamine (0.039 mL, 0.226 mmol) was stirred in DMF (1mL) at ambient temperature for 18 h. The reaction mixture was purifieddirectly by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The pure,product-containing fractions were combined and concentrated to give thetitle compound. MS: m/z=407 (M+1). MS: m/z=407.1500; calculatedm/z=407.1503 for C₂₅H₁₉N₄O₂.

Example 4

(±)-2-[Hydroxy(phenyl)methyl]-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,diastereomers A & B

To a stirred solution of(±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde(15 mg, 0.048 mmol, described in Intermediate 18) in CH₂Cl₂ (0.5 mL) at−78° C. was added phenylmagnesium bromide (1.0 M in THF, 0.33 mL, 0.33mmol) dropwise. The reaction mixture was stirred at −78° C. for 2 h andwas then allowed to warm to ambient temperature. The reaction wasquenched with H₂O and concentrated under reduced pressure. The residuewas purified by HPLC using a reversed phase C18 column and eluting witha gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The pure,product-containing fractions were combined and concentrated to give thetitle compound as the trifluoroacetate salt. MS: m/z=394 (M+1). HRMS:m/z=394.1565; calculated m/z=394.1550 for C₂₅H₂₀N₃O₂.

Example 5

(±)-Methyl3-(2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2-yl)benzoate

A stirred mixture of(±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(204 mg, 0.634 mmol, described in Intermediate 20),3-methoxycarbonylphenylboronic acid (229 mg, 1.27 mmol), PdCl₂(PPh₃)₂(44 mg, 0.063 mmol), and potassium carbonate (290 mg, 2.10 mmol), in1,2-dimethoxyethane (3 mL) and H₂O (1 mL) was heated at 80° C. for 18 h.The cooled mixture was partitioned between H₂O (40 mL) and EtOAc (40mL). The organic layer was removed and the aqueous phase was extractedfurther with EtOAc (40 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by HPLC using a reversed phase C18column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to5:95:0.1. The product-containing fractions were combined andconcentrated to give the title compound. MS: m/z=422 (M+1). HRMS: m/z422.1504; calculated m/z=422.1499 for C₂₆H₂₀N₃O₃.

Example 6

(±)-2-[(4-Methylphenyl)ethynyl]-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A stirred mixture of(±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(15 mg, 0.047 mmol, described in Intermediate 20), 4-ethynyltoluene (7mg, 0.061 mmol), PdCl₂(PPh₃)₂ (4 mg, 0.006 mmol), and diethylamine(0.073 mL, 0.70 mmol) in DMF (0.5 mL) was heated at 120° C. in amicrowave reactor for 5 min. The cooled mixture was partitioned betweensaturated aqueous NaHCO₃ (3 mL) and EtOAc (5 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Theproduct-containing fractions were combined and concentrated to give acrude product. This was further purified by silica gel chromatography,eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10, to give the titlecompound. MS: m/z=402 (M+1). HRMS: m/z=402.1609; calculated m/z=402.1601for C₂₇H₂₀N₃O.

Example 7

(7S-2-Benzyloxy-68-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′)-one

To a solution of benzyl alcohol (25 mg, 0.23 mmol) in DMF (1.8 mL), atambient temperature, was added sodium hydride (60% dispersion in mineraloil; 9 mg, 0.23 mmol). The resulting mixture was stirred for 10 min,then(7S)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(30 mg, 0.093 mmol, described in Intermediate 21) was added and theresulting mixture was stirred at ambient temperature for 1 h at ambienttemperature, then at 65° C. for 1 h. The reaction mixture was cooled,filtered, and purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Thepure, product-containing fractions were combined and concentrated togive the title compound. MS: m/z=394 (M+1). HRMS: m/z=394.1511;calculated m/z=394.1550 for C₂₅H₂₀N₃O₂.

Example 8

(7S)-2-Benzylamino-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of benzylamine (133 mg, 1.24 mmol), potassium carbonate (172mg, 1.24 mmol), and(7S)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(200 mg, 0.62 mmol, described in Intermediate 21) in1-methyl-2-pyrrolidinone (2 mL) was heated at 220° C. in a microwavereactor for 30 min. The cooled reaction mixture was poured into H₂O (20mL) and extracted with EtOAc (2×30 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Thepure, product-containing fractions were combined and concentrated togive the title compound as the trifluoroacetate salt. MS: m/z=393 (M+1).HRMS: m/z=393.1715; calculated m/z=393.1710 for C₂₅H₂₁N₄O.

Example 9

(7S)-2-{[(2-Oxo-2,3-dihydro-1,3-benzoxazol-7-yl)amino]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneStep A. 5-Chloro-7-nitro-1,3-benzoxazol-2(3H)-one

To a stirred solution of 2-amino-4-chloro-6-nitrophenol (2.00 g, 10.6mmol) in THF (50 mL) was added 1,1′-carbonyldiimidazole (2.06 g, 12.7mmol) and the resulting mixture was stirred at ambient temperature for 1h. The mixture was poured into 1 N hydrochloric acid and the precipitatewas isolated by filtration, washed with H₂O, then hexanes, and dried invacuo to give the title compound.

Step B. 7-Amino-1,3-benzoxazol-2(3H)-one

To a solution of 5-chloro-7-nitro-1,3-benzoxazol-2(3H)-one from Step A(1.10 g, 5.13 mmol) in EtOH (50 mL) was added 10% Pd/C (300 mg). Thereaction mixture was shaken in a Parr apparatus under a hydrogenatmosphere (40 p.s.i.) for 18 h, then filtered through a Celite pad,washing with EtOH, and the filtrate was concentrated under reducedpressure to give the title compound. MS: m/z=151 (M+1).

Step C.(7S)-2-{[(2-Oxo-2,3-dihydro-1,3-benzoxazol-7-yl)amino]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

Essentially following the procedures described for example 1, but using7-amino-1,3-benzoxazol-2(3B)-one from Step B in place of benzylamine,the title compound was obtained. MS: m/z=450 (M+1). HRMS: m/z=450.1563;calculated m/z=450.1561 for C₂₆H₂₀N₅O₃.

Example 10

2-[4-(4-methylpiperazin-1-yl)phenyl]-5,7-dihydro-1H-spiro[indeno[5,6-d]imidazole-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′)-one

A mixture of5,6-diamino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(30 mg, 0.11 mmol, described in Intermediate 13),4-(4-methylpiperazin-1-yl)benzoic acid [Mitskyavichyus & Sapiyanskaite,Chem. Heterocycl. Compd., 1985, 21, 1251-1254] (21 mg, 0.10 mmol), BOP(50 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.019 mL, 0.11 mmol)was stirred in, DMF (0.4 mL) at ambient temperature for 1 h, then AcOH(0.4 mL) was added and the resulting mixture was heated to 60° C. for 6h. The reaction mixture was purified directly by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. The pure, product-containingfractions were combined and concentrated to give the title compound asthe trifluoroacetate salt. MS: m/z=451 (M+1). HRMS: m/z=451.2247;calculated m/z=451.2241 for C₂₇H₂₇N₆O.

Examples 11-17

Essentially following the procedures outlined for example 1 thecompounds listed in Table 1 were prepared. The requisite amines werecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied.Relevant literature references are provided in the table.

TABLE 1

Example R^(b) MS (M + 1) Literature Reference 11

449 Mewshaw et al., Bioorg. Med. Chem. Lett., 1998, 8, 2675-2680. 12

462 Tamura et al., Chem. Ind. (London), 1975, 922-923. 13

484 14

462 15

450 Zinner & Wigert, Chem. Ber., 1960, 93, 1331-1339. 16

462 Becker, J. Am. Chem. Soc., 1955, 77, 6608-6610. 17

393

Examples 18-26

Essentially following the procedures outlined for example 1, but using(±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehydein place of(S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde,the compounds listed in Table 2 were prepared. The requisite amines werecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied.Relevant literature references are provided in the table.

TABLE 2

Example R^(b) MS (M + 1) Literature Reference 18

457 19

475 PCT Int. Appl. WO 2002048117 (2002) 20

437 21

423 22

433 23

433 24

433 25

460 26

514

Examples 27-37

Essentially following the procedures outlined for example 3, but using(±)-2′-oxo-1′,2,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid in place of(S)-2′-oxo-1,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid, the compounds listed in Table 3 were prepared. The requisiteamines were commercially available, described in the literature,synthesized according to methodology described herein (vide supra), orreadily synthesized by one skilled in the art of organic synthesis. Insome cases, straightforward protecting group strategies were applied.

TABLE 3

Example R^(b) MS (M + 1) 27

447 28

489 29

449 30

435 31

447 32

520 33

489 34

456 35

451 36

476 37

504

Examples 38-41

Essentially following the procedures outlined for example 4, thecompounds listed in Table 4 were prepared. The requisite Grignardreagents were commercially available, described in the literature,synthesized according to methodology described herein (vide supra), orreadily synthesized by one skilled in the art of organic synthesis. Insome cases, straightforward protecting group strategies were applied.

TABLE 4

Example R^(c) MS (M + 1) 38

408 39

386 40

358 41

400

Examples 42-48

Essentially following the procedures outlined for example 5, thecompounds listed in Table 5 were prepared. The requisite boronic acidswere commercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied.

TABLE 5

Example R^(a) MS (M + 1) 42

406 43

440 44

392 45

422 46

394 47

497 48

378

Examples 49-52

Essentially following the procedures outlined for example 6, thecompounds listed in Table 6 were prepared. The requisite alkynes werecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied.

TABLE 6

Example R^(a) MS (M + 1) 49

389 50

389 51

418 52

409

Examples 53-78

Essentially following the procedures outlined for example 10, thecompounds listed in Table 7 were prepared. The requisite acids werecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied.

TABLE 7

Example R^(d) MS (M + 1) 53

369 54

367 55

417 56

459 57

449 58

447 59

379 60

447 61

501 62

408 63

384 64

558 65

422 66

520 67

436 68

449 69

436 70

405 71

437 72

429 73

401 74

406 75

505 76

450 77

436 78

393

Example 79

(±)-N-(3,5-Difluorobenzyl)-2,2-dimethyl-N-[(2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl)methyl]propanamideStep A.(±)-3-{[(3,5-Difluorobenzyl)amino]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a stirred suspension of(±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-3-carbaldehyde(70.9 mg, 0.225 mmol, described in Intermediate 22) and3,5-difluorobenzyl amine (48.3 mg, 0.340 mmol) in chloroform (2.3 mL)was added sodium triacetoxyborohydride (76.3 mg, 0.36 mmol). After 22hours (50% conversion as judged by LCMS), the reaction mixture wasdiluted with chloroform (50 mL) and saturated sodium bicarbonate (20mL). The aqueous layer was extracted twice with chloroform (50 mL×2).The combined organics were dried over sodium sulfate. Filtration toremove drying agent gave a solution which was concentrated in vacuo togive a yellow residue. The impure product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:1 to 90:10,to give individually starting aldehyde and the title compound. MS:m/z=443 (M+1).

Step B.(±)-N-(3,5-Difluorobenzyl)-2,2-dimethyl-N-[(2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl)methyl]propanamide

To a suspension of(±)-3-{[(3,5-difluorobenzyl)amino]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step A (47.0 mg, 0.106 mmol) in DCM (1.5 mL) was added4-methylmorpholine (32.2 mg, 0.320 mmol). This mixture was sonicated toprovided a finely powdered suspension. After cooling to 0° C.,trimethylacetyl chloride (23.0 mg, 0.190 mmol) was added and the coolingbath was removed. After 23 hours, additional 4-methylmorpholine (2drops) and trimethylacetyl chloride (23.0 mg, 0.190 mmol) were added.After 7 hours, the reaction was quenched by the addition of one drop ofmethanol. This reaction mixture was applied to a silica gel column forpurification, eluting with a gradient of CH₂Cl₂:MeOH—100:1 to 94:6, togive the title compound as a white solid. MS: m/z=527 (M+1). HRMS:m/z=527.2253; calculated m/z=527.2253 for C₃₁H₂₉F₂N₄O₂.

Examples 80-87

Essentially following the procedures outlined for example 79, but usingIntermediate 23 in place of Intermediate 22, the compounds listed inTable 8 were prepared. The requisite amines and carboxylic acidderivatives were commercially available, described in the literature,synthesized according to methodology described herein (vide supra), orreadily synthesized by one skilled in the art of organic synthesis.

TABLE 8

Example R^(b) MS (M + 1) 80

505 81

541 82

593 83

579 84

523 85

519 86

535 87

477

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of the formula I:

wherein: B is a selected from: C₃₋₁₀cycloalkyl, phenyl, naphthyl,tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, azepanyl,azepinyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl,benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl,benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl,dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl,isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl,oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, phthalazinyl,piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl,triazolyl and triazolinyl, where B is linked to A¹ via a carbon atom inB and where B is unsubstituted or substituted with 1-5 substituentsindependently selected from R¹, R², R^(3a) and R^(3b), wherein R¹, R²,R^(3a) and R^(3b) are each independently selected from: (1) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-7 substituents eachindependently selected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (d)—C₃₋₆cycloalkyl, (e) phenyl or heterocycle, wherein heterocycle isselected from: azetidinyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, piperidinyl, azepanyl, azepinyl, piperazinyl,pyrazolyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, tetrazolyl,tetrahydrofuryl and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (ii) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (iii) halo, (iv) hydroxy, (v) trifluoromethyl, (vi)—OCF₃, (vii) oxo, (viii) amino, (ix) phenyl, and (x) benzyl, (f) —CO₂R⁹,wherein R⁹ is independently selected from: (i) hydrogen, (ii)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 substituents,substituents each independently selected from: (I) halo, (II) hydroxy,(III) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo,(IV) —C₃₋₆cycloalkyl, (V) phenyl, which is unsubstituted or substitutedwith 1-5 substituents each independently selected from:  (1) —C₁₋₄alkyl, (2) —O—C₁₋₆alkyl,  (3) halo,  (4) trifluoromethyl, and  (5) —OCF₃,(iii) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6substituents, substituents each independently selected from: (I) halo,(II) hydroxy, (III) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (IV) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, and (V) phenyl, and (iv) phenyl or heterocycle, whereinheterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl,triazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,tetrahydrofuryl, quinoxalinyl, piperidinyl, piperazinyl, andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (I) halo, (II)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo (III)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo (IV)—C₃₋₆cycloalkyl, (V) oxo, (VI) —CN, (VII) hydroxy, and (VIII) phenyl,(g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently selected from:(i) hydrogen, (ii) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-6 substituents each independently selected from: (I)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (II)halo, (III) hydroxy, (IV) —OCF₃, (V) —C₃₋₆cycloalkyl, and (VI) phenyl,(iii) —C₄₋₆cycloalkyl, (iv) phenyl, which is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (I)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (II)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (III)halo, (IV) hydroxy, (V) trifluoromethyl, (VI) —OCF₃, and (VII) CN, and(v) benzyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (I) —C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 halo, (II) —O—C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 halo, (III) halo, and (IV) trifluoromethyl, (vi)—COR⁹, and (vii) —SO₂R¹², (h) —SO₂R¹², wherein R¹² is selected from: (i)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 fluoro, (ii)—C₃₋₆cycloalkyl, (iii) phenyl or heterocycle, wherein heterocycle isselected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, whichphenyl or heterocycle is unsubstituted or substituted with 1-5substituents each independently selected from: (I) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (II) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (III) halo, (IV) hydroxy,(V) trifluoromethyl, (VI) —OCF₃, and (VII) CN, and (iv) benzyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (I) —C₁₋₁₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (II) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (III) halo, and (IV) trifluoromethyl, (i)—CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each independentlyselected from: (i) hydrogen, (ii) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 substituents each independently selected from: (I)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (II)halo, (III) hydroxy, (IV) —OCF₃, (V) —C₃₋₆cycloalkyl, and (VI) phenyl,(iii) —C₅₋₆cycloalkyl, which is unsubstituted or substituted with 1-5halo, (iv) phenyl, which is unsubstituted or substituted with 1-5substituents each independently selected from: (I) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (II) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (III) halo, (IV) hydroxy,(V) trifluoromethyl, (VI) —OCF₃, and (VII) CN, and (v) benzyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (I) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (II) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (III) halo, and (IV) trifluoromethyl, or where R^(10a)and R^(11a) join to form a ring selected from azetidinyl, pyrrolidinyl,piperidinyl, azepanyl, piperazinyl and morpholinyl, which ring isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (I) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (II) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (III) halo (IV) hydroxy (V) phenyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from:  (1) —C₁₋₄alkyl, which is unsubstituted or substitutedwith 1-3 halo,  (2) —O—C₁₋₄alkyl, which is unsubstituted or substitutedwith 1-3 halo, and  (3) halo, (VI) benzyl, which is unsubstituted orsubstituted with 1-5 substituents each independently selected from:  (1)—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 halo,  (2)—O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 halo, and (3) halo, (VII) —COR⁹, and (VIII) —SO₂R¹², (j) trifluoromethyl, (k)—OCO₂R⁹, (l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), (n)—(NR⁹)(CO)NR^(10a)R^(11a), (o) —SO₂ NR^(10a)R^(11a), and (p)—O—C₃₋₆cycloalkyl, (2) —C₃₋₆cycloalkyl, which is unsubstituted orsubstituted with 1-7 substituents each independently selected from: (a)halo, (b) hydroxy, (c) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (d) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (e) phenyl, which is unsubstituted or substituted with1-5 substituents each independently selected from: (i) —C₁₋₆alkyl, whichis unsubstituted or substituted with 1-5 halo, (ii) —O—C₁₋₆alkyl, whichis unsubstituted or substituted with 1-5 halo, (iii) halo, (iv) hydroxy,and (v) trifluoromethyl, (3) phenyl or heterocycle, wherein heterocycleis selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl,pyridazinyl, pyrrolidinyl, azetidinyl, azepanyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl,azepinyl, benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl, indolyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl,tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl, pyrrolyl, quinazolinyl,tetrahydrofuryl, thiazolinyl, purinyl, naphthyridinyl, quinoxalinyl,1,3-dioxolanyl, oxadiazolyl, piperidinyl, tetrahydropyranyl,tetrahydrothienyl, tetrahydrothiopyranyl, and morpholinyl, which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) —C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 substituents each independently selected from:(i) halo, (ii) hydroxy, (iii) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo, (iv) —C₃₋₆cycloalkyl, (v) phenyl, (vi)—CO₂R⁹, and (vii) —NR¹⁰R¹¹, (b) halo, (c) hydroxy, (d) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 halo, (e)—C₃₋₆cycloalkyl, (f) phenyl or heterocycle, wherein heterocycle isselected from: pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl,pyrimidinyl, pyrazinyl, thienyl and morpholinyl, which phenyl orheterocycle is unsubstituted or substituted with 1-substituents eachindependently selected from: (i) —C₁₋₆alkyl, (ii) —O—C₁₋₆alkyl, (iii)halo, (iv) hydroxy, and (v) trifluoromethyl, (g) —CO₂R⁹, (h) —(CO)R⁹,(i) —NR¹⁰R¹¹, (i) —CONR^(10a)R^(11a), (k) oxo (l) —SR¹², (m) —S(O)R¹²,(n) —SO₂R¹², (o) —SO₂NR^(10a)R^(11a), and (p) —CN, (4) halo, (5) oxo,(6) hydroxy, (7) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (a) halo, (b)hydroxy, (c) —C₃₋₆cycloalkyl, (d) phenyl, (e) —CO₂R⁹, and (f) —NR¹⁰R¹¹,(8) —CN, (9) —CO₂R⁹, (10) —NR¹⁰R¹¹, (11) —SR¹², (12) —S(O)R¹², (13)—SO₂R¹², (14) —SO₂NR^(10a)R^(11a), (15) —CONR^(10a)R^(11a), (16)—OCO₂R⁹, (17) —(NR^(10a))CO₂R⁹, (18) —O(CO)NR^(10a)R^(11a), (19)—(NR⁹)(CO)NR^(10a)R^(11a), (20) —(CO)—(CO)NR^(10a)R^(11a), and (21)—(CO)—(CO)OR⁹; or where R^(3a) and R^(3b) and the atom(s) to which theyare attached join to form a ring selected from cyclobutyl, cyclopentyl,cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl,piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, dihydropyranyl, thienyl, dihydrothienyl,tetrahydrothienyl, dihydrothiopyranyl, tetrahydrothiopyranyl,imidazolyl, imidazolinyl, and piperazinyl, which ring is unsubstitutedor substituted with 1-5 substituents each independently selected from:(a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3substituents each independently selected from: (i) halo, (ii) hydroxy,(iii) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 halo,(iv) —C₃₋₆cycloalkyl, (v) phenyl or heterocycle, wherein heterocycle isselected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, whichphenyl or heterocycle is unsubstituted or substituted with 1-5substituents each independently selected from: (I) —C₁₋₆alkyl, (II)—O—C₁₋₆alkyl, (III) halo, (IV) hydroxy, (V) trifluoromethyl, and (VI)—OCF₃, (vi) —CO₂R⁹, (vii) —NR¹⁰R¹¹, (viii) —SO₂R¹², (ix)—CONR^(10a)R^(11a), and (x) —(NR^(10a))CO₂R⁹, (b) phenyl or heterocycle,wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (i) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 fluoro, (ii) halo, (iii)hydroxy, (iv) —O—C₁₋₆alkyl, which is unsubstituted or substituted with1-6 fluoro, and (v) —C₃₋₆cycloalkyl, (c) halo, (d) —SO₂R¹², (e) hydroxy,(f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo,(g) —CN, (h) —COR¹², (i) —NR¹⁰R¹¹, (j) —CONR^(10a)R^(11a), (k) —CO₂R⁹,(l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), and (n)—(NR⁹)(CO)NR^(10a)R^(11a); A¹, A² and A³ are each independently selectedfrom: (1) a bond, (2) —CR¹³R¹⁴—, wherein R¹³ and R¹⁴ are eachindependently selected from: (a) hydrogen, (b) C₁₋₆ alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) —C₃₋₆cycloalkyl, (ii) —O—C₁₋₆alkyl, (iii) halo, (iv)hydroxy, and (v) phenyl, (c) hydroxy, and (d) halo, (3) —NR¹⁰—, (4)—CR¹³R¹⁴—NR¹⁰—, (5) —CR¹³R¹⁴—CH₂—, (6) —CH₂—CR¹³R¹⁴—, (7) —O—CR¹³R¹⁴—,(8) —CR¹³R¹⁴—O—, (9) —C≡C—, (10) —C(R¹³)═C(R¹⁴)—, and (II) —C(═O)—, orwherein one or two of A¹, A² and A³ are absent; A⁴, A⁵, A⁶ and A⁷ areeach independently selected from: (1) a bond, and (2) —CR¹³R¹⁴—, orwherein one of A⁴, A⁵, A⁶ and A⁷ is independently selected from: (i)—O—, (ii) —C(═O)—, and (iii) —N(R¹⁵)—, wherein R¹⁵ is selected from: (a)hydrogen, (b) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5substituents each independently selected from: (I) hydroxy, (II)—O—C₁₋₆alkyl, (III) halo, (IV) —C₃₋₆cycloalkyl, (V) trifluoromethyl, and(VI) phenyl, or wherein one or both of A⁴ and A⁷ are absent; E¹ and E⁵are each independently selected from: (1) ═C(R⁴)—, (2) —CR⁴R⁵—, (3)—C(═O)—, (4) —C(═S)—, (5)═N—, (6) ═N⁺(O⁻)—, (7) —N(R⁴)—, (8) —O—, (9)—S—, and (10) —SO₂—; E³ and E⁴ are each independently selected from: (1)a bond, (2) ═C(R⁴)—, (3) —CR⁴R⁵—, (4) —C(═O)—, (5) ═N⁺(O⁻)—, (6)—N(R⁴)—, and (7) —O—, or wherein one or both of E³ and E⁴ are absent; E²is selected from:

G¹ and G² are each independently selected from: (1) ═C(R⁴)—, (2) ═N—,and (3) ═N⁺(O⁻)—; J is selected from: (1) ═C(R^(6a))—, (2) —CR¹³R¹⁴—,and (3) —C(═O)—; K is selected from: (1) ═C(R^(6b))—, (2) —CR¹³R¹⁴—, (3)—C(═O)—, (4) —SO₂—, (5) ═N—, and (6) —N(R^(6b))—; R⁴ and R⁵ are eachindependently selected from: (1) hydrogen, (2) —C₁₋₄alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₆alkyl, (d)—C₃₋₆cycloalkyl, (e) phenyl, (f) —CONR_(10a)R^(11a), (g) —CO₂R⁹, and (h)—NR¹⁰R¹¹, (3) —C₃₋₆cycloalkyl, (4) phenyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from: (a)—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 fluoro, (b)halo, (c) hydroxy, and (d) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 fluoro, (5) halo, (6) hydroxy, (7) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (8) —CN, (9)—CO₂R⁹, (10) —NR¹⁰R¹¹, (11) —SO₂R¹², (12) —CONR^(10a)R^(11a), (13)—OCO₂R⁹, and (14) —(NR^(10a))CO₂R⁹; R^(6a) and R^(6b) are eachindependently selected from: (1) hydrogen; (2) —C₁₋₄alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —O—C₁₋₆alkyl, (c) —C₃₋₆cycloalkyl, (d)phenyl or heterocycle, wherein heterocycle is selected from: imidazolyl,oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (i) —C₁₋₆alkyl,(ii) —O—C₁₋₆alkyl, (iii) halo, (iv) hydroxy, (v) trifluoromethyl, and(vi) —OCF₃, (4) phenyl or heterocycle, wherein heterocycle is selectedfrom: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl,azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl,piperidinyl, and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) —C₁₋₄alkyl, which is unsubstituted or substitutedwith 1-5 fluoro, (b) halo, (c) hydroxy, (d) —O—C₁₋₄alkyl, which isunsubstituted or substituted with 1-5 fluoro, (e) —C₃₋₆cycloalkyl, and(f) phenyl, (5) halo, (6) hydroxy, (7) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (8) —CN, (9) —CO₂R⁹, (10)—NR¹⁰R¹¹, and (11) —CONR^(10a)R^(11a); or where R^(6a) and R^(6b) andthe atom(s) to which they are attached join to form a ring selected fromcyclopentenyl, cyclohexenyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, furanyl, dihydrofuranyl, dihydropyranyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thienyl,dihydrothienyl and dihydrothiopyranyl, which ring is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (a)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 substituentseach independently selected from: (i) halo, (ii) hydroxy, (iii)—O—C₁₋₆alkyl, (iv) —C₃₋₆cycloalkyl, (v) phenyl or heterocycle, whereinheterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (I) —C₁₋₆alkyl,(II) —O—C₁₋₆alkyl, (III) halo, (IV) hydroxy, (V) trifluoromethyl, and(VI) —OCF₃, (vi) —CO₂R⁹, (vii) —NR¹⁰R¹¹, (viii) —SO₂R¹², (ix)—CONR^(10a)R^(11a), and (x) —(NR^(10a))CO₂R⁹, (b) phenyl or heterocycle,wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (i) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 fluoro, (ii) halo, (iii)hydroxy, (iv) —O—C₁₋₆alkyl, which is unsubstituted or substituted with1-6 fluoro, and (v) —C₃₋₆cycloalkyl, (c) halo, (d) —SO₂R¹², (e) hydroxy,(f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo,(g) —CN, (h) —COR¹², (i) —NR¹⁰R¹¹, (i) —CONR^(10a)R^(11a), (k) —CO₂R⁹,(l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), (n)—(NR⁹)(CO)NR^(10a)R^(11a), and (o) oxo; or a pharmaceutically acceptablesalt thereof and individual enantiomers and diastereomers thereof. 2.The compound of claim 1 having the formula Ia:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 3. The compound of claim 1 having the formulaIb:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 4. The compound of claim 1 having the formulaIc:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 5. The compound of claim 1 having the formulaId:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 6. The compound of claim 1 having the formulaIe:

or a pharmaceutically acceptable salt salts thereof and individualenantiomers and diastereomers thereof.
 7. The compound of claim 1 havingthe formula If:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 8. The compound of claim 1 having the formulaIg:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 9. The compound of claim 1, wherein B isselected from the group consisting of: C₃₋₁₀cycloalkyl, phenyl,biphenyl, naphthyl, tetrahydronaphthyl, indanyl, indolyl, indolinyl,indazolyl, isoindolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl,morpholinyl, naphthyridinyl, piperidinyl, piperazinyl, pyrazinyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl,phthalazinyl, pyrazolyl, isoxazolinyl, indazolyl, benzoxazolyl,benzoxazolinyl, benzimidazolyl, benzimidazolinyl, thiazolyl, andthienyl, which is unsubstituted or substituted with 1-5 substituentsselected from R¹, R², R^(3a) and R^(3b).
 10. The compound of claim 8,wherein R¹, R², R^(3a) and R^(3b) are each independently selected from:(1) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5substituents each independently selected from: (a) halo, (b) hydroxy,(c) —O—C₁₋₆alkyl, (d) —C₃₋₆cycloalkyl, (e) phenyl or heterocycle,wherein heterocycle is selected from: pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl and morpholinyl, (f) —(NR^(10a))CO₂R⁹, and (l)NR¹⁰R¹¹, (2) C₃₋₆ cycloalkyl, (3) —OR⁹, (4) —OCF₃, (5) trifluoromethyl,(6) halo, (7) oxo, (8) hydroxy, (9) —CN, (10) —COR¹², (11) —CO₂R¹², (12)—CONR^(10a)R^(11a), (13) —NR¹⁰R¹¹, (14) phenyl, which is unsubstitutedor substituted with 1-5 substituents selected from: (a) C₁₋₆alkyl, (b)—O—C₁₋₆alkyl, (c) halo, (d) —OH, and (e) —CF₃, and (15) heterocycle,wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,thienyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrazolyl, ormorpholinyl, and which is unsubstituted or substituted with 1-5substituents selected from: (a) C₁₋₆alkyl, (b) —O—C₁₋₆alkyl, (c) halo,(d) —OH, and (e) —CF₃.
 11. The compound of claim 1, wherein R^(3a) andR^(3b) and the carbon atom(s) to which they are attached join to form aring selected from piperidinyl, cyclohexyl, cyclopentyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, andtetrahydrothiopyranyl, which ring is unsubstituted or substituted with1-3 substituents independently selected from: (a) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (i) halo, and (ii) phenyl, (b) phenyl or heterocycle,wherein heterocycle is selected from: pyridinyl, pyrimidinyl andpyrazinyl, (c) —CO₂R⁹, (d) hydroxy, and (e) oxo.
 12. The compound ofclaim 1, wherein R^(3a) and R^(3b) and the carbon atom(s) to which theyare attached are joined together to form a ring selected frompiperidinyl, cyclohexyl, tetrahydropyranyl, and tetrahydrothiopyranyl,which ring is unsubstituted or substituted with 1-3 substituentsindependently selected from: (a) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-3 substituents independently selected from: (i)fluoro, and (ii) phenyl, (b) —CO₂—C₁₋₄alkyl, (c) hydroxyl, and (d) oxo.13. The compound of claim 1, wherein A¹ is selected from a bond,—CR¹³R¹⁴—, —OCH₂—, —C≡C—, —CH₂—CH₂—, —C(H)═C(H)—, —NH— and -C(═O)—; A²is selected from a bond, CH₂, —CH₂—NH—, —C(═O)—, —C≡C—, —NH— and—CH₂—CH₂—; and A³ is selected from a bond, —CH₂—, —C(═O)— and —CH₂O—.14. The compound of claim 1, wherein A⁴ is selected from CH₂ and a bond;A⁵ is CH₂; A⁶ is CH₂; and A⁷ is selected from CH₂ and a bond.
 15. Thecompound of claim 1, wherein E¹ is selected from ═C(R⁴)—, —CR⁴R⁵—, ═N—,and —N(R⁴)—; E² is selected from ═C— and —N—; E³ is selected from abond, ═C(R⁴)—, —CR⁴R⁵—, ═N— and —N(R⁴)—; E⁴ is selected from a bond and—CH₂—; and E⁵ is selected from ═C(R⁴)—, —CR⁴R⁵—, ═N—, and —N(R⁴)—. 16.The compound of claim 1, wherein G¹ is ═C(H)— and G² is ═C(H)—.
 17. Thecompound of claim 1, wherein J is selected from ═C(R^(6a))— and —CH₂—;and K is selected from ═C(R^(6b))—, —CH₂— and —C(═O)—.
 18. (canceled)19. (canceled)
 20. (canceled)
 21. (canceled)
 22. (canceled) 23.(canceled)
 24. (canceled)
 25. A compound selected from:

or a pharmaceutically acceptable salt and individual stereoisomersthereof.
 26. A pharmaceutical composition which comprises an inertcarrier and the compound of claim 1, or a pharmaceutically acceptablesalt thereof and individual enantiomers and diastereomers thereof. 27.(canceled)
 28. A method for treating headache in a mammalian patient inneed of such which comprises administering to the patient atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof and individual enantiomers anddiastereomers thereof.
 29. (canceled)